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Myelodysplastic syndrome: review of the cytogenetic and molecular data
Critical Reviews in Oncology/Hematology 40 (2001) 229– 238 www.elsevier.com/locate/critrevonc
Myelodysplastic syndrome: review of the cytogenetic and molecular data Paulette Mhawech a, Abdus Saleem b,* a
b
Department of Pathology at the Uni6ersity Hospital of Gene6a, Gene6a, Switzerland Department of Pathology at Baylor College of Medicine and Methodist Hospital, One Baylor Plaza, Houston, TX 77030, USA Accepted 20 February 2001
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. Chromosome 5 abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. 5q-Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Other 5q-abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3. Chromosome 7 abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Monosomy 7 syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Juvenile myelomonocytic leukemia (JMML) . . . . . . . . . . . . . . . . . . . . . . . . . .
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4. 20q Deletion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5. 17p-Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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6. Trisomy 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7. Loss of Y chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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8. Deletion 12p13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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9. t(5; 12)(q33p13) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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10. Chromosome 3 abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. inv(3)(q21q26), t(3; 3)(q21; q26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. t(3:5)(q25.1; q34) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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11. t(11; 16)(q23; p13.3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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12. Isodicentric (X)(q13) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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13. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: + 1-713-7902439; fax: + 1-713-7931473. E-mail address: [email protected] (A. Saleem). 1040-8428/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 1 0 1 - 9
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Abstract Myelodysplastic syndrome (MDS) is a monoclonal disorder of the pluripotent stem cell that frequently evolves into acute leukemia. MDS is characterized by trilineage dysplasia and by ineffective hematopoiesis. The etiology of MDS is poorly understood. However, the frequent association of chromosomal abnormalities (deletions, inversions, translocations, trisomies and monosomies) with MDS suggests that an oncogene, or a tumor suppressor gene might be involved in the pathogenesis and evolution of this disorder. This review summarizes the clinical, laboratory, chromosomal and prognostic findings of some of the cytogenetic abnormalities such as; 20q deletion, chromosome 5, 7 and 3 abnormalities, 17p-syndrome, trisomy 8, and loss of Y chromosome. In addition, this review goes into the discussion of the most recent development in the field of molecular biology to understand some of the mechanisms resulting in the development and progression of MDS. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: MDS; Chromosomal abnormalities; Molecular features; Prognosis
1. Introduction Myelodysplastic syndrome (MDS) is a clonal disorder of the pluripotent hematopoietic stem cells. It affects mainly the middle age and elderly persons and is characterized by hypercellular bone marrow (BM), peripheral cytopenia and trilineage dysplasia. Although the majority of MDS patients have an increased BM cellularity, a small subgroup presents with an hypoplastic BM resulting in some diagnostic difficulties. MDS can be primary (de novo) or secondary to antineoplastic therapy, toxic agents and mutagens. Based on the number of ring sideroblasts, excess blasts and presence of monocytes, the French – American – British cooperative study group has classified MDS into five categories: (1) refractory anemia (RA); (2) refractory anemia with ring sideroblasts (RARS); (3) refractory anemia with excess blasts (RAEB); (4) refractory anemia with excess blasts in transformation (RAEB-t); and (5) chronic myelomonocytic leukemia (CMMoL) [1]. MDS is presumed to be a pre-leukemic condition, which progresses to acute leukemia in 30 – 40% of cases. Usually, it has unsatisfactory response to chemotherapy and BM transplant seems to be the only curative option for young patients with a suitable donor. De novo MDS shows cytogenetic abnormalities in 30 – 50% of cases. These abnormalities include monosomy or deletion of chromosome 5 and 7, inv(3), 20q deletion, 17p-syndrome, trisomy 8, loss of Y chromosome and others. In 1997, an international consensus score (International Prognostic Scoring System; IPSS) had defined prognostic factors that may predict outcome in patients with MDS. This scoring system is based on percentage of BM blasts, degree of cytopenia and chromosomal abnormalities [2]. In recent report, chromosomal abnormalities have been described to be a main prognostic factor for survival in MDS patients after allogeneic BM transplantation (BMT) [3]. The pathogenesis of MDS and its frequent progression to acute leukemia are not well-established. A tu-
mor-suppressor gene (TSG), an accumulation of new oncogenic fusion proteins, activation of oncogenes and mutations within the oncogenes have been suggested to play a role. On the other hand, MDS is characterized by an hypercellular BM with peripheral cytopenia. This paradox is mainly attributed to the high apoptotic activity in the BM that is due to the effect of different types of cytokines [4,5]. Thus, the increased proliferation rate in the BM space is quickly equilibrated by the increased cell death by apoptosis. As an end result and despite the high activity of the BM, the patients suffer from cytopenia. The aim of the current study is to summarize the chromosomal abnormalities in MDS, and whether these abnormalities can throw some light on the baffling course of the disease.
2. Chromosome 5 abnormalities The most common abnormalities of chromosome 5 include interstitial deletions of the long arm (5q-), monosomy, and unbalanced translocations. Partial deletion seems to present the most frequent aberration.
2.1. 5q-Syndrome Since its first description by Van Den Berghe et al. in 1974 [6], numerous cases of 5q-syndrome has been reported in the literature. However, the criteria used for 5q-syndrome had varied widely among the reported cases. To bring uniformity to these reports, Boultwood suggested that only those patients who present as primary MDS with RA-FAB subtype and who have 5q deletion as the sole karyotype abnormality should be included [7]. 5q-Syndrome has a striking female predominance with female to male ratio of about 3:1. It occurs in the elderly with median age of 60-years old. Patients with this syndrome present with macrocytic refractory anemia, slight leukopenia, high or normal
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platelet count, and numerous small hypolobulated megakaryocytes. Despite the thrombopoetic abnormality, patients do not suffer from signs and symptoms of hemorrhage or thrombosis. The majority of patients become red blood cell transfusion dependent as the disease progresses.
2.2. Other 5q-abnormalities It is more frequent in therapy-related MDS (tMDS). It is usually associated with partial or complete deletion of chromosome 7. Clinically, patients present with RA, RAEB, RAEB-t and acute myeloid leukemia (AML). A study by Pedersen et al. showed that the patients with del(5)(q13q33), in comparison to patients with different band deletion, are older in age, have longer survival time (27 vs. 8 months) and have less chromosomal aberrations. However, the frequency of progression to leukemia in those patients is equal to the frequency in other types of deletion [8]. However, some investigators had doubted in the existence of del(5)(ql3q33) as a distinct entity. This issue still has to be confirmed by further studies. Familial cases of MDS with 5q deletion have been reported which reinforce the concept of TSG hypothesis in some cases [9]. Deletion of long arm of chromosome 5 is interstitial in the majority of cases. Cytogenetic studies showed the occurrence of this deletion in both myeloid and erythroid progenitor cells. The long arm of chromosome 5 has a particular interest because it encodes many hematopoetic growth factors. The two breakpoints most frequently reported are, (1) proximal breakpoint at 5q12-14 and (2) distal breakpoint at 5q31-33. The invariable loss (90% of the cases) appears to be distal at 5q31. Another deletion 5q13.1 has been recently reported which appears to be of particular interest as it may encode a critical gene for leukemogenesis [10]. Among the most important genes mapped on chromosomes 5ql3-33 are listed from the centromeric to the telomeric order, interleukine-4 (IL-4), IL-5, interferon regulator factor 1 (IRF1), IL-3, CSF-2 (granulocyte-macrophage stimulating factor), IL-9, early growth response 1 (EGR-1), CDl4 (myeloid surface antigen) and, CSF-IR (formerly FMS). The interleukine family stimulates the proliferation of granulocytes. Cases with deletion of 5q segment encoding interleukine genes have been described. However, it is not known how a deletion of any of those genes will be sufficient to give rise to 5q-syndrome. The genes of great interest playing a role in the pathogenesis of 5q-syndrome and located at 5q31.1 are, IRF-1, EGR-l, and CSF-1R, IRF-1 is a transcription activator of interferon 1 genes, and has a growth inhibition and anti-oncogenic property [11]. Since 90% of the cases
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show deletion of IRF-l, it has been proposed that this gene may be a good candidate for a TSG. However, no mutation of IRF-1 has been found. EGR-1 is a zincfinger protein, and is required for the differentiation of monocyte–macrophage lineage. In addition, it plays a role in the differentiation of the myeloid blasts and is a positive regulator of cell growth. Due to its multiple function, it has been suggested that the deletion of EGR-l could play a role in myeloid malignancies [12,13]. Still, no mutation of EGR-1 has been described. CSF-1R plays a role in growth regulation of myeloid cells. Studies showed that this gene does not possess a function of a TSG, but it could be localized very close to a TSG [14,15]. Rare cases of 5q-syndrome undergo leukemic transformation and the prognosis is generally very good with median survival of about 28 months. With comparison to patients with 5q-syndrome, patients with 5qand with additional aberrations appear to have shorter survival time (6–11 months).
3. Chromosome 7 abnormalities Complete or partial deletion of long arm of chromosome 7 is a common finding in both MDS and AML. It is most frequently seen in association with other cytogenetic abnormalities such as 5q-. It has two peaks of age, one peak at first year of age and the second at sixth decades. 7q- can be seen in three groups: (1) de novo MDS (10% of the cases); (2) post-cytotoxic therapy for another malignancy and after occupational or environmental exposure to mutagens; and (3) patients with constitutional disorders, e.g. Fanconi anemia, neurofibromatosis (NF1) and congenital neutropenia. This third group is beyond the scope of this review and it will not be discussed. Familial cases in children with monsomy 7 have been well-documented [16]. In adults, 7q deletion will present as RAEB and RAEB-t. In children, the clinical presentation differs completely as rarely the FAB classification is of practical use, 7q del is found as the following disorders; adult-type MDS, monosomy 7 syndrome/juvenile myelomonocytic leukemia (JMML).
3.1. Monosomy 7 syndrome It is associated with loss of chromosome 7 and occurs in a variety of myeloid disorders including JMML. It occurs in young children with median age of 10 months, and has a male predominance. The clinical presentation is characterized by recurrent infection, skin rash, hepatosplenomegaly, and lymphadenopathy. The patients usually present with anemia, leukopenia and thrombocytopenia. The fetal hemoglobin level is often normal. Neutrophil function studies show defec-
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tive chemotaxis. BM examination may show mild to moderate reticulin fibrosis. Deletion of chromosome 7 is the only chromosomal abnormality seen.
3.2. Ju6enile myelomonocytic leukemia (JMML) JMML is a myeloproliferative disorder associated with monosomy 7 in 6– 24% of patients [17]. Like monosomy 7 syndrome, it occurs in young patients and has male predominance. The patients present with skin rash, hepatosplenomegaly, lymphadenopathy, anemia, leukopenia and thrombocytopenia. There is decrease of neutrophil alkaline phosphatase, increase of fetal hemoglobin level, and absence of Philadelphia chromosome. Monosomy 7 syndrome and JMML share many clinical and laboratory findings creating a controversy as whether they should be considered as two distinct entities. Cases of familial neurofibromatosis associated with monosomy 7 syndrome and JMML have been reported [18]. The deletion is frequently interstitial. Complete or partial loss of long arm of chromosome 7 affects both myeloid and erythroid cells. In a subset of cases, the deletion may affect B but not T-lymphocytes [19]. The frequent association of loss of chromosome 7 with myeloid leukemia led investigators to believe that loss of 7 could lead to a loss of a gene that regulates growth and differentiation of the myeloid cells [20]. However, loss of chromosome 7 might be necessary but not sufficient for the disease progression as it occurs late in the disease. The majority of the cases show two major breakpoints: (1) proximal breakpoint at ql1-22 and (2) distal breakpoint at q31-36. The critical region that is commonly deleted and may encode a TSG is 7q 22 [21]. At the present time no candidate TSG has been implicated in the pathogenesis. The genes of interest which have been mapped on chromosome 7q are; erythropoetin (EPO) and plasmin activator inhibitor (PLANHI) gene on 7q21.3-22, asparagine synthase gene (ASNS) on 7q22.1 and T-cell receptor b (TCRB) on 7q35. The ASNS, a cell cycle control enzyme could be a good candidate for a TSG, but no breakpoint interrupting directly this gene has been found [22]. A recent work by Johnson et al. documented a new breakpoint at 7q22.1 and suggested that this segment of the chromosome might has a significant role in myeloid malignancies [23]. RAS oncogene can be activated most frequently by point mutation in adult MDS. RAS activation has been documented in high percentage of MDS patients with monosomy 7 indicating that these two (RAS and monosomy 7) can co-operate in the process of leukemogenesis in MDS [24]. However, the mechanism explaining how loss of chromosome 7 may lead to RAS activation is not known. Activation of RAS gene by
point mutation in children is less common and in some cases, the RAS gene is deregulated by other mechanisms such as neurofibromatosis-1 (NF1) gene. NF-1 gene has a function of a TSG. It encodes a GTPase activation protein (GAP), which negatively regulates RAS activation [25]. Loss of NF1 gene as seen in monosomy 7/JMML neurofibromatosis children developing acute leukemia, leads to GAP deactivating and consequently to RAS activation [26,27]. MDS with monosomy 7 is very aggressive disease and the median survival time is of 9 months. The rate of evolution to leukemia is 33% of the cases if 7q- is the sole anomaly and of 71% if there association with other chromosomal abnormalities. Also, both JMML and monosomy 7 syndrome have bad prognosis with rapid transformation into acute leukemia and very short survival time. BM transplant is the treatment of choice in most cases in these very young patients.
4. 20q Deletion 20q Deletion is seen in 10% myeloproliferative disorders (MPD), most frequently in polycythemia vera, MDS 2 – 5%, and AML 3%. This deletion is characterized by a lower incidence of anemia, low percentage of BM blasts and favorable outcome. 20q Deletion can occur solely or in association with other chromosomal anomalies such as del 5q, del 7q, monosomy 7 and trisomy 8. Deletion of chromosome 20 is interstitial and occurs in pluripotent stem cells giving rise to myeloid and lymphoid cells. A study by Asimakopoulos et al. identified the presence of 20q deletion in the BM metaphase but not in the peripheral blood. In these circumstances, caution should be made when interpreting the peripheral blood as absence of 20q deletion in the peripheral blood may not reflect the chromosomal anomaly existing in the BM. The most likely explanation of this discrepancy, as speculated by the authors, is the selective destruction/retention of granulocytes within the BM [28]. There is presence of both centromeric and telomeric breakpoints with the most common deleted region spans between 20q11.2 and q13.2. Subsequently, the critical deleted region is reduced to the interval of 18cM between SRC and D20S17 in MPD and to a smaller region extending between D20S174 and D20S17 in MDS [29,30]. Genes of interest located at chromosome 20 are, PLC1 (phospholipase C d) on q12-13.1, adenosine deaminase (ADA) on 20q12-13.11, topoisomerase 1 (TOP1) on q12-13.2, hematopoetic cell kinase (HCK) on 20q11-12, SRC (human homologue of Rous sarcoma virus) on q11.2, p107 on q11.2, RPN2 (human ribophorin II) on q11.2, growth hormone releasing factor (GHRF) on q11, and the myeloid leukemia gene
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being located between RPN2 and D20S17 (20q12) [31]. The non-random occurrence of 20q deletion in various myeloid disorders raises the question of the presence of TSG on long arm of chromosome 20. The candidate TSGs mapped on 20q are 1/SRC oncogene mapped on 20q11.2, it encodes a non-receptor tyrosine kinase and has been implicated in cell growth regulation. 2/HCK located on 20q11-12, is also a non-receptor tyrosine kinase and is expressed in hematopoetic cells. 3/p107 gene is homologous to the protein encoded by the retinoblastoma gene. However, all these three genes are located outside the deleted region. The possible candidate tumor suppressor genes which lie within the deleted region, 1/A transcription regulator, TPO1 and 2/phospholipase C d (PLC1) which plays a role in signal transduction [29]. The responsible TSGs in MDS and MPD has yet to be defined. Patients with 20q deletion have favorable outcome with low incidence of progression to AML and long survival median of 42 months. Only patients with 5qsyndrome have more prolonged survival time than those with deletion of 20q.
5. 17p-Syndrome The deletion of short arm of chromosome 17 is most frequently seen in t-MDS and rarely in de novo MDS. Clinically, it is characterized by dysgranulopoesis, pseudo-Pelger–Huet anomaly and small vacuolation of the neutrophils. p53 is A nuclear phosphoprotein located at 17p13.1. It regulates DNA replication, cell proliferation and cell death, which makes it an excellent TSG. When DNA is damaged, p53 switch-off replication allowing the cells the time to repair their damage, for this reason it has been called ‘guardian genome’ [32]. With loss of p53 by mutation or deletion, as has been documented in varieties of cancer, the function of p53 is compromised leading to genomic instability and contributing to clonal evolution and tumor progression [33]. 17p-Syndrome seems to fit Knudson’s two-hit theory of oncogenes, where one p53 allele located at chromosome 17p is lost by deletion and the second allele is mutated [34]. Although p53 mutation has a low incidence in MDS, its presence in this subset of MDS implicates that p53 may play a role at least in a small fraction of MDS cases.
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additional chromosome 8) or mosaic (presence of normal cells in addition of cells caring the trisomy 8). Acquired form of trisomy 8 is the most frequent form seen in MDS (11% of cases). Trisomy 8 as the sole chromosomal abnormalities appears to have a male predominance accounting for two-third of cases [35]. Clinically, it is not associated with any specific FAB group and it is usually presented with cytopenia of one or three cell lines. Constitutional trisomy 8 mosaicism (CT8M) syndrome has a rare occurrence. Patients with this syndrome have a broad phenotypic spectrum ranging from dysmorphic features to near-normal. In addition, the majority of the patients present with mild to moderate mental retardation. Patients with CT8M syndrome are very hard to classify in the FAB subtypes. They have a high pre-disposition to develop different types of malignancies in particular myeloid and proliferative disorders [36,37]. Trisomy 8 affects the cells at the colony-forming unit of granulocyte–erythrocyte–macrophage–megakaryocyte (CFU-GEMM) level or earlier, but neither progenitor stem cells (CD34+ , thy-l+ ) nor the lymphoid cells seems to be affected [38]. Despite the high incidence of trisomy 8 in myeloid malignancies and the presence of two important genes mapped on chromosome 8; myelofibrosis (MOS) gene on 8q11 and MYC gene on 3q24, the molecular aspects of this chromosomal abnormality have not attracted a lot of attention. This fact can be attributed to the significant fluctuation of trisomy 8 seen in many reports showing a complete disappearance of trisomy 8 clones in the course of the disease. In addition, this fluctuation seems to be not related to the number of blasts in the BM nor to the disease progression [39,40]. Thus, these findings suggest that trisomy 8 is not closely related to the pathogenesis of MDS and chromosome 8 may not hold the key genes responsible for MDS. Fluorescence in situ-hybridization (FISH) is very reliable method for trisomy 8 detection as it may show positive results when the conventional cytogenetic studies are normal [41]. Trisomy 8 belongs to the IPSS intermediate-risk cytogenetic subgroup. A recent study by Sole´ et al. found that patients with trisomy 8 as the sole chiomosomal abnormality have a significant risk of leukemic transformation and worse behavior than expected in the IPSS intermediate risk-group [42]. Their findings still have to be confirmed by larger study groups. Patients with CT8M have a rapid progression to leukemia [37].
6. Trisomy 8 Trisomy 8 is the most frequent numerical aberration seen in myeloid disorders, such as MDS, MPD, and AML. It can be constitutional or acquired, and it can be seen in full condition (all analyzed cells have the
7. Loss of Y chromosome As a general rule, the detection of chromosomal abnormalities in the BM implicates malignant or pre-
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malignant conditions. Loss of Y chromosome as the sole cytogenetic abnormality is one exception to the rule, as it can be seen in the BM of healthy old men. It can also occur in MDS, AML and MPD. The frequencies of Y loss in normal, MDS and AML cases are 7.7, 10.7 and 3.7%, respectively [43]. This incidence increases significantly in males after 70 years of age and with age in both, malignant and pre-malignant conditions. Although loss of Y chromosome has been seen in young patients with t(8;21) of AML M2 AFB-subtype, this occurrence is though to be as a secondary event [44]. The hypothesis of the association of increase incidence of Y loss with age can be attributed to a cumulative effect of loss of Y chromosome from individual cells through errors in cell division or to a proliferative advantage of Y-clone which gradually replace the XY cells [43]. Most studies concluded that loss of Y is not involved in the leukemic process, as there is no consistent relationship between disease progression and remission, and percentage of cells with loss of Y [45]. The clinical significance of Y loss is still subject of controversy. Investigators reported that MDS patients with Y loss have better prognosis and longer survival rate [46]. Others showed an aggressive clinical course and an intermediate prognosis [47]. Finally, other investigators showed that loss of Y has no impact on prognosis [44].
telomeric to TEL and the second at KIP1 or centromeric to KIP1. Finally, the last could be a gene, not yet identified, which may lie on the smallest region of overlap located between TEL and KIP1 [50]. However, no mutations of either TEL or KIP1 genes have been identified. According to the IPSS, patients with p12 deletion as the sole chromosomal anomaly are in the intermediate risk cytogenetic-subgroup [2]. Once again, Sole´ et al. showed that patients with 12p13 del have similar survival rate as patients with normal karyotype and they tend to have better survival than patients in the IPSS intermediate risk group [42].
9. t(5;12)(q33p13) t(5;12) is a rare cytogenetic anomaly mostly seen in CMML and it can also occur in MPD. TEL gene is located at 12p13 and has a negative role in transcription regulation. The platelet derived growth factor receptor b (PDGFRB) is located at 5q33, it is a plasma membrane receptor and has an endogenous tyrosine kinase activity. t(5;12) Results in a fusion transcript between the TEL gene and the PDGFRG gene. The TEL –PDGFRB fusion product seems to have an oncogenic potential [51]. t(5;2) and its variant (10;12)(q24;p13) can be identified by florescence in situ hybridization (FISH) method using the appropriate probe [52].
8. Deletion 12p13 10. Chromosome 3 abnormalities Unbalanced translocation and interstitial deletion of short arm of chromosome 12 have been found in wide varieties of myeloid and lymphoid malignancies. It occurs in MDS, t-MDS, MPD, AML and acute lymphoid leukemia (ALL). Clinically, MDS patients may present with RAEB, RAEB-t and CMML. Located on 12p13 region is the TEL gene (translocation ets leukemia). It is a member of ets family transcription factors. It is a negative regulator of transcription and most likely a good candidate TSG. Other gene mapped on 12p13 is the KIP1 gene, which encodes the p27 protein. KIP1/p27 is one of the cyclindependent kinases (CKds) inhibitors, has a crucial role in the passage of checkpoints cell cycle and plays an important role in inhibiting cell proliferation [48]. Thus, p27/KIPl is an excellent TSG and loss of its function has been documented in cancer progression [49]. Sato et al. has documented the smallest region of overlap (SRO) on 12p13, which is bordered by TEL gene on the telomeric side and by KIPl on the centromeric side with a distance not more than 2.9 Mbp apart. The authors suggested that the deletion could have more than one target. The first deletion could be at TEL gene or
There is a wide variety of cytogenetic abnormalities involving the chromosome 3 and present in MDS such as; del 3p, inv(3)(q21q26), t(3;3)(q21;q26), ins or dup3(q21;q26), t(3;12)(q26;p13), t(3;21) (q26;q22), and t(3;5)(q25.1;q34). They share many clinical and prognostic features, (1) commonly seen in t-MDS; (2) frequently seen in association with other chromosomal abnormalities, most commonly with monosomy 7/7qand 5q; (3) have poor prognosis and short survival; (4) resistance to conventional chemotherapy. We will discuss two of these chromosomal abnormalities that have particular clinical and molecular features.
10.1. in6(3)(q21q26), t(3;3)(q21;q26) Paracentric inversions and homologous translocation of chromosome 3 involving q21 and q26 are reported in AML, blastic crisis of chronic myeloid leukemia (CML) and in MDS. Besides the typical features shared with other chromosomal anomalies involving chromosome 3, patients with 3q21q26 seems to present few characteristic clinical features. They are relatively of young
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age (B 55-years old), are mostly female (female to male ratio of 2/1). In addition, they present with normal to elevated platelet counts (on average\ 100 000 mm − 3), and dysplasia of the erythroid, myeloid cells and especially megakaryocytes [53]. The abnormal hematopoiesis seen in all three of cell lines implicates that 3q21q26 most probably involved the pluripotent stem cells. The gene located within the 3q21 and 3qter band are; transferrin on q21, lactoferrin q21– q23, transferrin receptor q26.2qter, melanotransferrin q27-29, CALLA-CD10 on q21-q27, and esotropic virus integration site 1 gene (EVI-l) on q26. However, none of these genes has been implicated in the pathogenesis. Although the etiology of the dysmegakaryopoesis is unknown, two suggestions have been proposed, (1) the juxtaposition of q21 and q26 bands may present a critical event in the dysregulation of the pluripotent stem cells; and (2) unidentified gene located on 3q21 may have a role in the pathogenesis of the abnormal thrombopoesis [54,55].
10.2. t(3:5)(q25.1;q34) It can occur in MDS and AML. The NPM gene is located at 3q25.1. It is a nucleocytoplasmic shuttle protein that plays a role in transporting ribosomal nucleoproteins (rRNPs) between the nucleolus and the cytoplasm during the ribosomal assembly. The myelodysplasia/myeloid leukemia factor 1 (MLF-1) gene is located at 5q24. It encodes a cytoplasmic protein and could have a role in DNA replication and cell regulation. The translocation 3;5 results in a NPM-MLF1 fusion gene product which can alter DNA replication, RNA processing or gene expression in a way that influence the control of cell growth [56].
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11. t(11;16)(q23;p13.3) t(11; 16) is seen in t-ALL, t-AML and in t-MDS. Patients present with RAEB-t or CMML FAB-subtypes. The involvement of 11q23 translocation is seen after treatment with DNA-topoisomerase II inhibitors and most notably after epipodophyllotoxins when used at high doses [57]. The 11q23 translocation involves most commonly the MLL breakpoint cluster region, also called ALL, HTRX and HRX. The normal function of human MLL gene, as well as the mechanism by which dysregulation of this gene could contribute to leukemia are unknown. The breakpoint on chromosome 16 involves the CBP gene, a transcriptional co-activator. It is capable of interaction with a broad spectrum of transcription factors and has a histone acetyltransferase activity resulting to an elevation of gene expression [58]. Thus, CBP gene may have a role in cell cycle regulation. Mutation of CBP has been found in individuals with Rubstein– Taybi syndrome who are at increased risk of developing cancer [59]. These data suggest that the CBP gene can be a TSG. The MLL-CBP fusion leads to structural alteration of the CBP gene and consequently to cell cycle deregulation [60], a hypothesis which may explain the leukemic transformation in patients with t(11;16).
12. Isodicentric (X)(q13) It is a rare finding in MDS and can also be found in MPS and AML. (X)(q13) is the most common breakpoint involving the X chromosome. It occurs exclusively in elderly female having more than 65years old and it is characterized by the frequent association with BM iron accumulation [61]. It has been
Table 1 Summary of the most pertinent clinical and laboratory data of the chromosomal abnormalities in myelodysplastic syndromea Chromosomal abnormalities
Age/sex
Clinical features
Laboratory findings
5q-syndrome
F/60 years
–
Monosomy 7
M/10 months
JMML
M/10 months
Recurrent infection, skin rash HSM, lymphadenopathy Skin rash, HSM lymphadenopathy
20q Deletion 17p-Syndrome
– –
– –
CT8M inv(3)(q21q26) idic(x)(q13)
New-born F/B55 years F/\65 years
Dysmorphic features, mental retardation – –
Refractory anemia, leukopenia, N–H platelets small hypolobulated megakaryocytes Pancytopenia, N FHb, defect of chemotatic function of neutrophils, fibrosis in the BM Pancytopenia ¡NALP, FHb, absence philadelphia chromosome Low degree of anemia, low percentage of BM blasts Dysgranulopoesis, pseudo-Pelger–Huet anomaly, small vacuolated neutrophils – N to platelet count, Marked dysmegakeryopoesis Iron accumulation in the BM
a CT8M, constitutional trisomy 8 mosaicsm; F, female; M, male; HSM, hepatosplenomegaly; FHb, F hemoglobin; N, normal; H, high; BM, bone marrow; NALP, neutrophilic alkaline phosphatase; BM, bone marrow; –, not specific.
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Table 2 Summary of target chromosomal segments and their candidate tumor suppressor genes involved in the pathogenesis of myelodysplastic syndrome Chromosomal abnormalities
Chromosomal segments
Candidate tumor suppressor genes and their role
Chromosome 5 abnormalities Chromosome 7 abnormalities
5q31.1
IRF-1, transcription activator of interferon 1; EGR-1, differentiation of monocyte-macrophages lineage and myeloid blasts, positive regulation of cell growth; CSF-1R, growth regulation of myaloid cells ASNS, control of the cell cycle
7q21–22
7q22.1 20q 12–13.2 20q12–13.1 17p-Syndrome 17q13.1 12p13 Deletion 12p13 t(5;12) (q33;p13) 12p13 5q33 t(3;5) 3q25.1 (q25.1;q34) 5q24 t(11;16) 11q23 (q23;p13.3) 16p13.3 20q Deletion
Unknown gene, significant role in myeloid malignancies TPO1, regulator of transcription PLC1, has a role in signal transduction p53, Regulation of DNA replication, cell proliferation and cell death KIP/27, inhibitor of cell proliferation; TEL, negative regulation of transcription TEL, negative regulation of transcription PDGFRB, activation of tyrosine kinase NPM, transport of ribosomal nucleoprotein MLF-1, DNA replication and cell regulation MLL, unknown mechanism CBP, regulation of cell cycle
suggested that the chromosomal abnormality may occur in early progenitor cells. The prognosis is variable as some authors reported cases with favorable clinical course and others with aggressive clinical outcome and very short survival [61,62].
13. Conclusion MDS is an indolent disorder affecting mainly the elderly and progresses in acute leukemia in 30– 40% of the cases. In the present work, we reviewed some of a long list of chromosomal abnormalities in MDS, discussing their clinical, laboratory, molecular and prognostic aspects. In the majority of chromosomal abnormalities, the clinical presentations and laboratory features are not specific, except for few such as 5q-syndrome, monosomy 7 and JMML, 17p-syndrome, 20q del, CT8M, idic(X)(q13) and inv(3) (Table 1). The prognosis is usually poor except for few such as 5q syndrome, other 5q abnormalities, 20q del, 12p13 del and loss of Y chromosome. The molecular data are reviewed and summarized in Table 2. Taken all these molecular data together, we concluded that TSG alone can not explain the etiology of MDS and that is for many reasons. First, chromosomal loss occurs later in the disease progression and some of them may even regress during the course of the disease. Second, chromosomal abnormalities occur in 40% of MDS, so what explanation we have for the 60% remaining cases. Third, chromosomal abnormalities are present in some clones but not in all. Finally, at the exception of 17p-syndrome, no mutation of TSG has been found to fit the two-hit theory for tumor initiation and progression. MDS is a clonal disorder of BM
stem cells where all lineages are descendants of one single diseased parent stem cell. Thus, the TSG theory does not explain the ‘initial event’ that lead to the growth advantage of stem cells and consequently to monoclonal hematopoiesis. In our opinion, the data presented to us indicates that TSG might have a role in the progression of the disease in some cases. On the other hand, N-ras oncogene mutation is frequently seen in MDS. It occurs late in the course of the disease and is associated with shorter survival and rapid progression to leukemia [63,64]. In addition, the incidence of p53 mutation is very low as it is seen early in MDS and is associated with poor prognosis and shorter survival [65]. These data suggested that oncogene activation could play a partial role in leukemic progression of particular molecular abnormalities in MDS. Even though the advance of molecular biology had shed some lights on some aspects of the pathogenesis of MDS, we still are left with many unanswered questions. We hope that future research will solve some of the mystery surrounding this complex disorder and help to find the optimal cure for many patients. References [1] Bennett JM, Catovsky D, Daniel M, et al. Proposals for classification of myelodysplastic syndromes. Br J Haematol 1982;51:189 – 99. [2] Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluation prognosis in myelodysplastic syndromes. Blood 1997;89:2079 – 88. [3] Nevill TJ, Fung HC, Shepherd JD, et al. Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive outcome after allogeneic bone marrow transplantation. Blood 1998;92:1910 – 7.
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Myelodysplastic syndrome: review of the cytogenetic and molecular data Paulette Mhawech a, Abdus Saleem b,* a
b
Department of Pathology at the Uni6ersity Hospital of Gene6a, Gene6a, Switzerland Department of Pathology at Baylor College of Medicine and Methodist Hospital, One Baylor Plaza, Houston, TX 77030, USA Accepted 20 February 2001
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
230
2. Chromosome 5 abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. 5q-Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Other 5q-abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
230 230 231
3. Chromosome 7 abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Monosomy 7 syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Juvenile myelomonocytic leukemia (JMML) . . . . . . . . . . . . . . . . . . . . . . . . . .
231 231 232
4. 20q Deletion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
232
5. 17p-Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
233
6. Trisomy 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
233
7. Loss of Y chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
233
8. Deletion 12p13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
234
9. t(5; 12)(q33p13) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
234
10. Chromosome 3 abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. inv(3)(q21q26), t(3; 3)(q21; q26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. t(3:5)(q25.1; q34) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
234 234 235
11. t(11; 16)(q23; p13.3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
235
12. Isodicentric (X)(q13) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
235
13. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
236
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: + 1-713-7902439; fax: + 1-713-7931473. E-mail address: [email protected] (A. Saleem). 1040-8428/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 1 0 1 - 9
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Abstract Myelodysplastic syndrome (MDS) is a monoclonal disorder of the pluripotent stem cell that frequently evolves into acute leukemia. MDS is characterized by trilineage dysplasia and by ineffective hematopoiesis. The etiology of MDS is poorly understood. However, the frequent association of chromosomal abnormalities (deletions, inversions, translocations, trisomies and monosomies) with MDS suggests that an oncogene, or a tumor suppressor gene might be involved in the pathogenesis and evolution of this disorder. This review summarizes the clinical, laboratory, chromosomal and prognostic findings of some of the cytogenetic abnormalities such as; 20q deletion, chromosome 5, 7 and 3 abnormalities, 17p-syndrome, trisomy 8, and loss of Y chromosome. In addition, this review goes into the discussion of the most recent development in the field of molecular biology to understand some of the mechanisms resulting in the development and progression of MDS. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: MDS; Chromosomal abnormalities; Molecular features; Prognosis
1. Introduction Myelodysplastic syndrome (MDS) is a clonal disorder of the pluripotent hematopoietic stem cells. It affects mainly the middle age and elderly persons and is characterized by hypercellular bone marrow (BM), peripheral cytopenia and trilineage dysplasia. Although the majority of MDS patients have an increased BM cellularity, a small subgroup presents with an hypoplastic BM resulting in some diagnostic difficulties. MDS can be primary (de novo) or secondary to antineoplastic therapy, toxic agents and mutagens. Based on the number of ring sideroblasts, excess blasts and presence of monocytes, the French – American – British cooperative study group has classified MDS into five categories: (1) refractory anemia (RA); (2) refractory anemia with ring sideroblasts (RARS); (3) refractory anemia with excess blasts (RAEB); (4) refractory anemia with excess blasts in transformation (RAEB-t); and (5) chronic myelomonocytic leukemia (CMMoL) [1]. MDS is presumed to be a pre-leukemic condition, which progresses to acute leukemia in 30 – 40% of cases. Usually, it has unsatisfactory response to chemotherapy and BM transplant seems to be the only curative option for young patients with a suitable donor. De novo MDS shows cytogenetic abnormalities in 30 – 50% of cases. These abnormalities include monosomy or deletion of chromosome 5 and 7, inv(3), 20q deletion, 17p-syndrome, trisomy 8, loss of Y chromosome and others. In 1997, an international consensus score (International Prognostic Scoring System; IPSS) had defined prognostic factors that may predict outcome in patients with MDS. This scoring system is based on percentage of BM blasts, degree of cytopenia and chromosomal abnormalities [2]. In recent report, chromosomal abnormalities have been described to be a main prognostic factor for survival in MDS patients after allogeneic BM transplantation (BMT) [3]. The pathogenesis of MDS and its frequent progression to acute leukemia are not well-established. A tu-
mor-suppressor gene (TSG), an accumulation of new oncogenic fusion proteins, activation of oncogenes and mutations within the oncogenes have been suggested to play a role. On the other hand, MDS is characterized by an hypercellular BM with peripheral cytopenia. This paradox is mainly attributed to the high apoptotic activity in the BM that is due to the effect of different types of cytokines [4,5]. Thus, the increased proliferation rate in the BM space is quickly equilibrated by the increased cell death by apoptosis. As an end result and despite the high activity of the BM, the patients suffer from cytopenia. The aim of the current study is to summarize the chromosomal abnormalities in MDS, and whether these abnormalities can throw some light on the baffling course of the disease.
2. Chromosome 5 abnormalities The most common abnormalities of chromosome 5 include interstitial deletions of the long arm (5q-), monosomy, and unbalanced translocations. Partial deletion seems to present the most frequent aberration.
2.1. 5q-Syndrome Since its first description by Van Den Berghe et al. in 1974 [6], numerous cases of 5q-syndrome has been reported in the literature. However, the criteria used for 5q-syndrome had varied widely among the reported cases. To bring uniformity to these reports, Boultwood suggested that only those patients who present as primary MDS with RA-FAB subtype and who have 5q deletion as the sole karyotype abnormality should be included [7]. 5q-Syndrome has a striking female predominance with female to male ratio of about 3:1. It occurs in the elderly with median age of 60-years old. Patients with this syndrome present with macrocytic refractory anemia, slight leukopenia, high or normal
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platelet count, and numerous small hypolobulated megakaryocytes. Despite the thrombopoetic abnormality, patients do not suffer from signs and symptoms of hemorrhage or thrombosis. The majority of patients become red blood cell transfusion dependent as the disease progresses.
2.2. Other 5q-abnormalities It is more frequent in therapy-related MDS (tMDS). It is usually associated with partial or complete deletion of chromosome 7. Clinically, patients present with RA, RAEB, RAEB-t and acute myeloid leukemia (AML). A study by Pedersen et al. showed that the patients with del(5)(q13q33), in comparison to patients with different band deletion, are older in age, have longer survival time (27 vs. 8 months) and have less chromosomal aberrations. However, the frequency of progression to leukemia in those patients is equal to the frequency in other types of deletion [8]. However, some investigators had doubted in the existence of del(5)(ql3q33) as a distinct entity. This issue still has to be confirmed by further studies. Familial cases of MDS with 5q deletion have been reported which reinforce the concept of TSG hypothesis in some cases [9]. Deletion of long arm of chromosome 5 is interstitial in the majority of cases. Cytogenetic studies showed the occurrence of this deletion in both myeloid and erythroid progenitor cells. The long arm of chromosome 5 has a particular interest because it encodes many hematopoetic growth factors. The two breakpoints most frequently reported are, (1) proximal breakpoint at 5q12-14 and (2) distal breakpoint at 5q31-33. The invariable loss (90% of the cases) appears to be distal at 5q31. Another deletion 5q13.1 has been recently reported which appears to be of particular interest as it may encode a critical gene for leukemogenesis [10]. Among the most important genes mapped on chromosomes 5ql3-33 are listed from the centromeric to the telomeric order, interleukine-4 (IL-4), IL-5, interferon regulator factor 1 (IRF1), IL-3, CSF-2 (granulocyte-macrophage stimulating factor), IL-9, early growth response 1 (EGR-1), CDl4 (myeloid surface antigen) and, CSF-IR (formerly FMS). The interleukine family stimulates the proliferation of granulocytes. Cases with deletion of 5q segment encoding interleukine genes have been described. However, it is not known how a deletion of any of those genes will be sufficient to give rise to 5q-syndrome. The genes of great interest playing a role in the pathogenesis of 5q-syndrome and located at 5q31.1 are, IRF-1, EGR-l, and CSF-1R, IRF-1 is a transcription activator of interferon 1 genes, and has a growth inhibition and anti-oncogenic property [11]. Since 90% of the cases
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show deletion of IRF-l, it has been proposed that this gene may be a good candidate for a TSG. However, no mutation of IRF-1 has been found. EGR-1 is a zincfinger protein, and is required for the differentiation of monocyte–macrophage lineage. In addition, it plays a role in the differentiation of the myeloid blasts and is a positive regulator of cell growth. Due to its multiple function, it has been suggested that the deletion of EGR-l could play a role in myeloid malignancies [12,13]. Still, no mutation of EGR-1 has been described. CSF-1R plays a role in growth regulation of myeloid cells. Studies showed that this gene does not possess a function of a TSG, but it could be localized very close to a TSG [14,15]. Rare cases of 5q-syndrome undergo leukemic transformation and the prognosis is generally very good with median survival of about 28 months. With comparison to patients with 5q-syndrome, patients with 5qand with additional aberrations appear to have shorter survival time (6–11 months).
3. Chromosome 7 abnormalities Complete or partial deletion of long arm of chromosome 7 is a common finding in both MDS and AML. It is most frequently seen in association with other cytogenetic abnormalities such as 5q-. It has two peaks of age, one peak at first year of age and the second at sixth decades. 7q- can be seen in three groups: (1) de novo MDS (10% of the cases); (2) post-cytotoxic therapy for another malignancy and after occupational or environmental exposure to mutagens; and (3) patients with constitutional disorders, e.g. Fanconi anemia, neurofibromatosis (NF1) and congenital neutropenia. This third group is beyond the scope of this review and it will not be discussed. Familial cases in children with monsomy 7 have been well-documented [16]. In adults, 7q deletion will present as RAEB and RAEB-t. In children, the clinical presentation differs completely as rarely the FAB classification is of practical use, 7q del is found as the following disorders; adult-type MDS, monosomy 7 syndrome/juvenile myelomonocytic leukemia (JMML).
3.1. Monosomy 7 syndrome It is associated with loss of chromosome 7 and occurs in a variety of myeloid disorders including JMML. It occurs in young children with median age of 10 months, and has a male predominance. The clinical presentation is characterized by recurrent infection, skin rash, hepatosplenomegaly, and lymphadenopathy. The patients usually present with anemia, leukopenia and thrombocytopenia. The fetal hemoglobin level is often normal. Neutrophil function studies show defec-
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tive chemotaxis. BM examination may show mild to moderate reticulin fibrosis. Deletion of chromosome 7 is the only chromosomal abnormality seen.
3.2. Ju6enile myelomonocytic leukemia (JMML) JMML is a myeloproliferative disorder associated with monosomy 7 in 6– 24% of patients [17]. Like monosomy 7 syndrome, it occurs in young patients and has male predominance. The patients present with skin rash, hepatosplenomegaly, lymphadenopathy, anemia, leukopenia and thrombocytopenia. There is decrease of neutrophil alkaline phosphatase, increase of fetal hemoglobin level, and absence of Philadelphia chromosome. Monosomy 7 syndrome and JMML share many clinical and laboratory findings creating a controversy as whether they should be considered as two distinct entities. Cases of familial neurofibromatosis associated with monosomy 7 syndrome and JMML have been reported [18]. The deletion is frequently interstitial. Complete or partial loss of long arm of chromosome 7 affects both myeloid and erythroid cells. In a subset of cases, the deletion may affect B but not T-lymphocytes [19]. The frequent association of loss of chromosome 7 with myeloid leukemia led investigators to believe that loss of 7 could lead to a loss of a gene that regulates growth and differentiation of the myeloid cells [20]. However, loss of chromosome 7 might be necessary but not sufficient for the disease progression as it occurs late in the disease. The majority of the cases show two major breakpoints: (1) proximal breakpoint at ql1-22 and (2) distal breakpoint at q31-36. The critical region that is commonly deleted and may encode a TSG is 7q 22 [21]. At the present time no candidate TSG has been implicated in the pathogenesis. The genes of interest which have been mapped on chromosome 7q are; erythropoetin (EPO) and plasmin activator inhibitor (PLANHI) gene on 7q21.3-22, asparagine synthase gene (ASNS) on 7q22.1 and T-cell receptor b (TCRB) on 7q35. The ASNS, a cell cycle control enzyme could be a good candidate for a TSG, but no breakpoint interrupting directly this gene has been found [22]. A recent work by Johnson et al. documented a new breakpoint at 7q22.1 and suggested that this segment of the chromosome might has a significant role in myeloid malignancies [23]. RAS oncogene can be activated most frequently by point mutation in adult MDS. RAS activation has been documented in high percentage of MDS patients with monosomy 7 indicating that these two (RAS and monosomy 7) can co-operate in the process of leukemogenesis in MDS [24]. However, the mechanism explaining how loss of chromosome 7 may lead to RAS activation is not known. Activation of RAS gene by
point mutation in children is less common and in some cases, the RAS gene is deregulated by other mechanisms such as neurofibromatosis-1 (NF1) gene. NF-1 gene has a function of a TSG. It encodes a GTPase activation protein (GAP), which negatively regulates RAS activation [25]. Loss of NF1 gene as seen in monosomy 7/JMML neurofibromatosis children developing acute leukemia, leads to GAP deactivating and consequently to RAS activation [26,27]. MDS with monosomy 7 is very aggressive disease and the median survival time is of 9 months. The rate of evolution to leukemia is 33% of the cases if 7q- is the sole anomaly and of 71% if there association with other chromosomal abnormalities. Also, both JMML and monosomy 7 syndrome have bad prognosis with rapid transformation into acute leukemia and very short survival time. BM transplant is the treatment of choice in most cases in these very young patients.
4. 20q Deletion 20q Deletion is seen in 10% myeloproliferative disorders (MPD), most frequently in polycythemia vera, MDS 2 – 5%, and AML 3%. This deletion is characterized by a lower incidence of anemia, low percentage of BM blasts and favorable outcome. 20q Deletion can occur solely or in association with other chromosomal anomalies such as del 5q, del 7q, monosomy 7 and trisomy 8. Deletion of chromosome 20 is interstitial and occurs in pluripotent stem cells giving rise to myeloid and lymphoid cells. A study by Asimakopoulos et al. identified the presence of 20q deletion in the BM metaphase but not in the peripheral blood. In these circumstances, caution should be made when interpreting the peripheral blood as absence of 20q deletion in the peripheral blood may not reflect the chromosomal anomaly existing in the BM. The most likely explanation of this discrepancy, as speculated by the authors, is the selective destruction/retention of granulocytes within the BM [28]. There is presence of both centromeric and telomeric breakpoints with the most common deleted region spans between 20q11.2 and q13.2. Subsequently, the critical deleted region is reduced to the interval of 18cM between SRC and D20S17 in MPD and to a smaller region extending between D20S174 and D20S17 in MDS [29,30]. Genes of interest located at chromosome 20 are, PLC1 (phospholipase C d) on q12-13.1, adenosine deaminase (ADA) on 20q12-13.11, topoisomerase 1 (TOP1) on q12-13.2, hematopoetic cell kinase (HCK) on 20q11-12, SRC (human homologue of Rous sarcoma virus) on q11.2, p107 on q11.2, RPN2 (human ribophorin II) on q11.2, growth hormone releasing factor (GHRF) on q11, and the myeloid leukemia gene
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being located between RPN2 and D20S17 (20q12) [31]. The non-random occurrence of 20q deletion in various myeloid disorders raises the question of the presence of TSG on long arm of chromosome 20. The candidate TSGs mapped on 20q are 1/SRC oncogene mapped on 20q11.2, it encodes a non-receptor tyrosine kinase and has been implicated in cell growth regulation. 2/HCK located on 20q11-12, is also a non-receptor tyrosine kinase and is expressed in hematopoetic cells. 3/p107 gene is homologous to the protein encoded by the retinoblastoma gene. However, all these three genes are located outside the deleted region. The possible candidate tumor suppressor genes which lie within the deleted region, 1/A transcription regulator, TPO1 and 2/phospholipase C d (PLC1) which plays a role in signal transduction [29]. The responsible TSGs in MDS and MPD has yet to be defined. Patients with 20q deletion have favorable outcome with low incidence of progression to AML and long survival median of 42 months. Only patients with 5qsyndrome have more prolonged survival time than those with deletion of 20q.
5. 17p-Syndrome The deletion of short arm of chromosome 17 is most frequently seen in t-MDS and rarely in de novo MDS. Clinically, it is characterized by dysgranulopoesis, pseudo-Pelger–Huet anomaly and small vacuolation of the neutrophils. p53 is A nuclear phosphoprotein located at 17p13.1. It regulates DNA replication, cell proliferation and cell death, which makes it an excellent TSG. When DNA is damaged, p53 switch-off replication allowing the cells the time to repair their damage, for this reason it has been called ‘guardian genome’ [32]. With loss of p53 by mutation or deletion, as has been documented in varieties of cancer, the function of p53 is compromised leading to genomic instability and contributing to clonal evolution and tumor progression [33]. 17p-Syndrome seems to fit Knudson’s two-hit theory of oncogenes, where one p53 allele located at chromosome 17p is lost by deletion and the second allele is mutated [34]. Although p53 mutation has a low incidence in MDS, its presence in this subset of MDS implicates that p53 may play a role at least in a small fraction of MDS cases.
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additional chromosome 8) or mosaic (presence of normal cells in addition of cells caring the trisomy 8). Acquired form of trisomy 8 is the most frequent form seen in MDS (11% of cases). Trisomy 8 as the sole chromosomal abnormalities appears to have a male predominance accounting for two-third of cases [35]. Clinically, it is not associated with any specific FAB group and it is usually presented with cytopenia of one or three cell lines. Constitutional trisomy 8 mosaicism (CT8M) syndrome has a rare occurrence. Patients with this syndrome have a broad phenotypic spectrum ranging from dysmorphic features to near-normal. In addition, the majority of the patients present with mild to moderate mental retardation. Patients with CT8M syndrome are very hard to classify in the FAB subtypes. They have a high pre-disposition to develop different types of malignancies in particular myeloid and proliferative disorders [36,37]. Trisomy 8 affects the cells at the colony-forming unit of granulocyte–erythrocyte–macrophage–megakaryocyte (CFU-GEMM) level or earlier, but neither progenitor stem cells (CD34+ , thy-l+ ) nor the lymphoid cells seems to be affected [38]. Despite the high incidence of trisomy 8 in myeloid malignancies and the presence of two important genes mapped on chromosome 8; myelofibrosis (MOS) gene on 8q11 and MYC gene on 3q24, the molecular aspects of this chromosomal abnormality have not attracted a lot of attention. This fact can be attributed to the significant fluctuation of trisomy 8 seen in many reports showing a complete disappearance of trisomy 8 clones in the course of the disease. In addition, this fluctuation seems to be not related to the number of blasts in the BM nor to the disease progression [39,40]. Thus, these findings suggest that trisomy 8 is not closely related to the pathogenesis of MDS and chromosome 8 may not hold the key genes responsible for MDS. Fluorescence in situ-hybridization (FISH) is very reliable method for trisomy 8 detection as it may show positive results when the conventional cytogenetic studies are normal [41]. Trisomy 8 belongs to the IPSS intermediate-risk cytogenetic subgroup. A recent study by Sole´ et al. found that patients with trisomy 8 as the sole chiomosomal abnormality have a significant risk of leukemic transformation and worse behavior than expected in the IPSS intermediate risk-group [42]. Their findings still have to be confirmed by larger study groups. Patients with CT8M have a rapid progression to leukemia [37].
6. Trisomy 8 Trisomy 8 is the most frequent numerical aberration seen in myeloid disorders, such as MDS, MPD, and AML. It can be constitutional or acquired, and it can be seen in full condition (all analyzed cells have the
7. Loss of Y chromosome As a general rule, the detection of chromosomal abnormalities in the BM implicates malignant or pre-
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malignant conditions. Loss of Y chromosome as the sole cytogenetic abnormality is one exception to the rule, as it can be seen in the BM of healthy old men. It can also occur in MDS, AML and MPD. The frequencies of Y loss in normal, MDS and AML cases are 7.7, 10.7 and 3.7%, respectively [43]. This incidence increases significantly in males after 70 years of age and with age in both, malignant and pre-malignant conditions. Although loss of Y chromosome has been seen in young patients with t(8;21) of AML M2 AFB-subtype, this occurrence is though to be as a secondary event [44]. The hypothesis of the association of increase incidence of Y loss with age can be attributed to a cumulative effect of loss of Y chromosome from individual cells through errors in cell division or to a proliferative advantage of Y-clone which gradually replace the XY cells [43]. Most studies concluded that loss of Y is not involved in the leukemic process, as there is no consistent relationship between disease progression and remission, and percentage of cells with loss of Y [45]. The clinical significance of Y loss is still subject of controversy. Investigators reported that MDS patients with Y loss have better prognosis and longer survival rate [46]. Others showed an aggressive clinical course and an intermediate prognosis [47]. Finally, other investigators showed that loss of Y has no impact on prognosis [44].
telomeric to TEL and the second at KIP1 or centromeric to KIP1. Finally, the last could be a gene, not yet identified, which may lie on the smallest region of overlap located between TEL and KIP1 [50]. However, no mutations of either TEL or KIP1 genes have been identified. According to the IPSS, patients with p12 deletion as the sole chromosomal anomaly are in the intermediate risk cytogenetic-subgroup [2]. Once again, Sole´ et al. showed that patients with 12p13 del have similar survival rate as patients with normal karyotype and they tend to have better survival than patients in the IPSS intermediate risk group [42].
9. t(5;12)(q33p13) t(5;12) is a rare cytogenetic anomaly mostly seen in CMML and it can also occur in MPD. TEL gene is located at 12p13 and has a negative role in transcription regulation. The platelet derived growth factor receptor b (PDGFRB) is located at 5q33, it is a plasma membrane receptor and has an endogenous tyrosine kinase activity. t(5;12) Results in a fusion transcript between the TEL gene and the PDGFRG gene. The TEL –PDGFRB fusion product seems to have an oncogenic potential [51]. t(5;2) and its variant (10;12)(q24;p13) can be identified by florescence in situ hybridization (FISH) method using the appropriate probe [52].
8. Deletion 12p13 10. Chromosome 3 abnormalities Unbalanced translocation and interstitial deletion of short arm of chromosome 12 have been found in wide varieties of myeloid and lymphoid malignancies. It occurs in MDS, t-MDS, MPD, AML and acute lymphoid leukemia (ALL). Clinically, MDS patients may present with RAEB, RAEB-t and CMML. Located on 12p13 region is the TEL gene (translocation ets leukemia). It is a member of ets family transcription factors. It is a negative regulator of transcription and most likely a good candidate TSG. Other gene mapped on 12p13 is the KIP1 gene, which encodes the p27 protein. KIP1/p27 is one of the cyclindependent kinases (CKds) inhibitors, has a crucial role in the passage of checkpoints cell cycle and plays an important role in inhibiting cell proliferation [48]. Thus, p27/KIPl is an excellent TSG and loss of its function has been documented in cancer progression [49]. Sato et al. has documented the smallest region of overlap (SRO) on 12p13, which is bordered by TEL gene on the telomeric side and by KIPl on the centromeric side with a distance not more than 2.9 Mbp apart. The authors suggested that the deletion could have more than one target. The first deletion could be at TEL gene or
There is a wide variety of cytogenetic abnormalities involving the chromosome 3 and present in MDS such as; del 3p, inv(3)(q21q26), t(3;3)(q21;q26), ins or dup3(q21;q26), t(3;12)(q26;p13), t(3;21) (q26;q22), and t(3;5)(q25.1;q34). They share many clinical and prognostic features, (1) commonly seen in t-MDS; (2) frequently seen in association with other chromosomal abnormalities, most commonly with monosomy 7/7qand 5q; (3) have poor prognosis and short survival; (4) resistance to conventional chemotherapy. We will discuss two of these chromosomal abnormalities that have particular clinical and molecular features.
10.1. in6(3)(q21q26), t(3;3)(q21;q26) Paracentric inversions and homologous translocation of chromosome 3 involving q21 and q26 are reported in AML, blastic crisis of chronic myeloid leukemia (CML) and in MDS. Besides the typical features shared with other chromosomal anomalies involving chromosome 3, patients with 3q21q26 seems to present few characteristic clinical features. They are relatively of young
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age (B 55-years old), are mostly female (female to male ratio of 2/1). In addition, they present with normal to elevated platelet counts (on average\ 100 000 mm − 3), and dysplasia of the erythroid, myeloid cells and especially megakaryocytes [53]. The abnormal hematopoiesis seen in all three of cell lines implicates that 3q21q26 most probably involved the pluripotent stem cells. The gene located within the 3q21 and 3qter band are; transferrin on q21, lactoferrin q21– q23, transferrin receptor q26.2qter, melanotransferrin q27-29, CALLA-CD10 on q21-q27, and esotropic virus integration site 1 gene (EVI-l) on q26. However, none of these genes has been implicated in the pathogenesis. Although the etiology of the dysmegakaryopoesis is unknown, two suggestions have been proposed, (1) the juxtaposition of q21 and q26 bands may present a critical event in the dysregulation of the pluripotent stem cells; and (2) unidentified gene located on 3q21 may have a role in the pathogenesis of the abnormal thrombopoesis [54,55].
10.2. t(3:5)(q25.1;q34) It can occur in MDS and AML. The NPM gene is located at 3q25.1. It is a nucleocytoplasmic shuttle protein that plays a role in transporting ribosomal nucleoproteins (rRNPs) between the nucleolus and the cytoplasm during the ribosomal assembly. The myelodysplasia/myeloid leukemia factor 1 (MLF-1) gene is located at 5q24. It encodes a cytoplasmic protein and could have a role in DNA replication and cell regulation. The translocation 3;5 results in a NPM-MLF1 fusion gene product which can alter DNA replication, RNA processing or gene expression in a way that influence the control of cell growth [56].
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11. t(11;16)(q23;p13.3) t(11; 16) is seen in t-ALL, t-AML and in t-MDS. Patients present with RAEB-t or CMML FAB-subtypes. The involvement of 11q23 translocation is seen after treatment with DNA-topoisomerase II inhibitors and most notably after epipodophyllotoxins when used at high doses [57]. The 11q23 translocation involves most commonly the MLL breakpoint cluster region, also called ALL, HTRX and HRX. The normal function of human MLL gene, as well as the mechanism by which dysregulation of this gene could contribute to leukemia are unknown. The breakpoint on chromosome 16 involves the CBP gene, a transcriptional co-activator. It is capable of interaction with a broad spectrum of transcription factors and has a histone acetyltransferase activity resulting to an elevation of gene expression [58]. Thus, CBP gene may have a role in cell cycle regulation. Mutation of CBP has been found in individuals with Rubstein– Taybi syndrome who are at increased risk of developing cancer [59]. These data suggest that the CBP gene can be a TSG. The MLL-CBP fusion leads to structural alteration of the CBP gene and consequently to cell cycle deregulation [60], a hypothesis which may explain the leukemic transformation in patients with t(11;16).
12. Isodicentric (X)(q13) It is a rare finding in MDS and can also be found in MPS and AML. (X)(q13) is the most common breakpoint involving the X chromosome. It occurs exclusively in elderly female having more than 65years old and it is characterized by the frequent association with BM iron accumulation [61]. It has been
Table 1 Summary of the most pertinent clinical and laboratory data of the chromosomal abnormalities in myelodysplastic syndromea Chromosomal abnormalities
Age/sex
Clinical features
Laboratory findings
5q-syndrome
F/60 years
–
Monosomy 7
M/10 months
JMML
M/10 months
Recurrent infection, skin rash HSM, lymphadenopathy Skin rash, HSM lymphadenopathy
20q Deletion 17p-Syndrome
– –
– –
CT8M inv(3)(q21q26) idic(x)(q13)
New-born F/B55 years F/\65 years
Dysmorphic features, mental retardation – –
Refractory anemia, leukopenia, N–H platelets small hypolobulated megakaryocytes Pancytopenia, N FHb, defect of chemotatic function of neutrophils, fibrosis in the BM Pancytopenia ¡NALP, FHb, absence philadelphia chromosome Low degree of anemia, low percentage of BM blasts Dysgranulopoesis, pseudo-Pelger–Huet anomaly, small vacuolated neutrophils – N to platelet count, Marked dysmegakeryopoesis Iron accumulation in the BM
a CT8M, constitutional trisomy 8 mosaicsm; F, female; M, male; HSM, hepatosplenomegaly; FHb, F hemoglobin; N, normal; H, high; BM, bone marrow; NALP, neutrophilic alkaline phosphatase; BM, bone marrow; –, not specific.
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Table 2 Summary of target chromosomal segments and their candidate tumor suppressor genes involved in the pathogenesis of myelodysplastic syndrome Chromosomal abnormalities
Chromosomal segments
Candidate tumor suppressor genes and their role
Chromosome 5 abnormalities Chromosome 7 abnormalities
5q31.1
IRF-1, transcription activator of interferon 1; EGR-1, differentiation of monocyte-macrophages lineage and myeloid blasts, positive regulation of cell growth; CSF-1R, growth regulation of myaloid cells ASNS, control of the cell cycle
7q21–22
7q22.1 20q 12–13.2 20q12–13.1 17p-Syndrome 17q13.1 12p13 Deletion 12p13 t(5;12) (q33;p13) 12p13 5q33 t(3;5) 3q25.1 (q25.1;q34) 5q24 t(11;16) 11q23 (q23;p13.3) 16p13.3 20q Deletion
Unknown gene, significant role in myeloid malignancies TPO1, regulator of transcription PLC1, has a role in signal transduction p53, Regulation of DNA replication, cell proliferation and cell death KIP/27, inhibitor of cell proliferation; TEL, negative regulation of transcription TEL, negative regulation of transcription PDGFRB, activation of tyrosine kinase NPM, transport of ribosomal nucleoprotein MLF-1, DNA replication and cell regulation MLL, unknown mechanism CBP, regulation of cell cycle
suggested that the chromosomal abnormality may occur in early progenitor cells. The prognosis is variable as some authors reported cases with favorable clinical course and others with aggressive clinical outcome and very short survival [61,62].
13. Conclusion MDS is an indolent disorder affecting mainly the elderly and progresses in acute leukemia in 30– 40% of the cases. In the present work, we reviewed some of a long list of chromosomal abnormalities in MDS, discussing their clinical, laboratory, molecular and prognostic aspects. In the majority of chromosomal abnormalities, the clinical presentations and laboratory features are not specific, except for few such as 5q-syndrome, monosomy 7 and JMML, 17p-syndrome, 20q del, CT8M, idic(X)(q13) and inv(3) (Table 1). The prognosis is usually poor except for few such as 5q syndrome, other 5q abnormalities, 20q del, 12p13 del and loss of Y chromosome. The molecular data are reviewed and summarized in Table 2. Taken all these molecular data together, we concluded that TSG alone can not explain the etiology of MDS and that is for many reasons. First, chromosomal loss occurs later in the disease progression and some of them may even regress during the course of the disease. Second, chromosomal abnormalities occur in 40% of MDS, so what explanation we have for the 60% remaining cases. Third, chromosomal abnormalities are present in some clones but not in all. Finally, at the exception of 17p-syndrome, no mutation of TSG has been found to fit the two-hit theory for tumor initiation and progression. MDS is a clonal disorder of BM
stem cells where all lineages are descendants of one single diseased parent stem cell. Thus, the TSG theory does not explain the ‘initial event’ that lead to the growth advantage of stem cells and consequently to monoclonal hematopoiesis. In our opinion, the data presented to us indicates that TSG might have a role in the progression of the disease in some cases. On the other hand, N-ras oncogene mutation is frequently seen in MDS. It occurs late in the course of the disease and is associated with shorter survival and rapid progression to leukemia [63,64]. In addition, the incidence of p53 mutation is very low as it is seen early in MDS and is associated with poor prognosis and shorter survival [65]. These data suggested that oncogene activation could play a partial role in leukemic progression of particular molecular abnormalities in MDS. Even though the advance of molecular biology had shed some lights on some aspects of the pathogenesis of MDS, we still are left with many unanswered questions. We hope that future research will solve some of the mystery surrounding this complex disorder and help to find the optimal cure for many patients. References [1] Bennett JM, Catovsky D, Daniel M, et al. Proposals for classification of myelodysplastic syndromes. Br J Haematol 1982;51:189 – 99. [2] Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluation prognosis in myelodysplastic syndromes. Blood 1997;89:2079 – 88. [3] Nevill TJ, Fung HC, Shepherd JD, et al. Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive outcome after allogeneic bone marrow transplantation. Blood 1998;92:1910 – 7.
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