- Email: [email protected]
Trisomy 14 in refractory anemia with excess of blasts in transformation
Trisomy 14 in Refractory Anemia with Excess of Blasts in Transformation Oskar A. Haas, Ulrich J iger, Peter Ambros, and Ingrid Pabinger
ABSTRACT: Trisomy 14 was demonstrated on four occasions over a 2-year period in the bone marrow cells of a 63-year-old patient with refractory anemia with excess of blasts in transformation (RAEB-t). Trisomy 14 as the sole karyotype abnormality has been documented in only six malignancies, namely, in two cases of acute leukemias, one Philadelphia-negative chronic myeloid leukemia, one pancytopenia, and in two colonic polyps. In hematologic neoplasms, this rare primary change preferentially occurs in elderly adults and seems exclusively associated with the myeloid cell lineage.
INTRODUCTION The gain of one chromosome as the sole cytogenetic change has been reported in 6%-7% of all h u m a n neoplasms [1]. Chromosomes most often affected are #8, #9, #12, and #21. The frequency of such simple trisomies varies widely w i t h i n different neoplasms, but particular chromosomes are significantly associated with specific disease entities [1]. Trisomy 8, for example, is particularly common within a variety of myeloid neoplasias. Trisomy 4 and 22, on the other hand, are rather rare and their distinct connection with certain morphologic subgroups of acute myeloid leukemia has only been recognized recently [2-4]. We report herein the occurrence of trisomy 14 in a case of preleukemia that seems to be another rare but specific karyotype abnormality of myeloid disorders. CASE REPORT A 61-year-old m a n with a 3-month history of normochromic anemia was referred to the First Medical University Clinic, Vienna, for further diagnostic evaluation and treatment. With the exception of diabetes mellitus, arterial occlusion symptoms, and angina pectoris, his personal and family medical history was unremarkable. On admission his RBC was 2.3 x 1012/L, hemoglobin 100 g/L, WBC 2.6 x 109/L with 2% band forms, 38% segmented neutrophils, 2% eosinophils, 48% lymphocytes; platelets 61 × 109/L. No ringed sideroblasts were observed. Neither hepatospleno-
From the Departmentof Geneticsand Endocrinology,RoswellPark MemorialInstitute, Buffalo,NY (O. A. H.), the First Medical Clinic, Universityof Vienna (U. J., I. P.), and the St. Anna Children's Hospital (O. A. H., P. A.) Vienna,Austria. Address requests for reprints to Dr. Oskar A. Haas, St. A n n a Children's Hospital, Kinderspitalgasse 6, A-1090 Vienna, Austria. Received March 18, 1987; accepted April 28, 1987.
315 © 1987 Elsevier SciencePublishingCo., Inc. 52 VanderbiltAve., New York, NY 10017
Cancer Genet Cytogenet29:315-318(1987) 0165-4608/87/$03.50
316
O . A . Haas et al. megaly nor l y m p h a d e n o p a t h y was evident. Bone marrow aspirate and b i o p s y showed h y p e r c e l l u l a r i t y with dyserythro-, dysgranulo-, and dysmegakaryocytopoiesis and 10% m y e l o i d blasts in w h i c h occasional Auer rods were present. According to the criteria of the FAB classification [5], refractory anemia with excess of blasts in transformation (RAEB-t) was diagnosed. Within the following months the patient was transfused with RBC and platelet concentrates w h e n e v e r necessary. Two months after diagnosis, therapy with low-dose c y t o s i n e - a r a b i n o s i d e was initiated and repeated 6 months later. It lead to only a slight reduction of the blast cells, but to a partial remission of the peripheral red blood cell and platelet count. Two years after diagnosis the patient remains in stable condition.
CYTOGENETIC STUDIES
Chromosome analyses were performed on bone marrow short-term cultures 6, 12, 22, and 26 months after diagnosis. The samples were cultured for 24 hours, processed according to standard cytogenetic techniques, and stained with t r y p s i n Giemsa as previously described [6]. At least 20 metaphases were karyotyped on each occasion. In a d d i t i o n to normal male metaphases, a h y p e r d i p l o i d clone with 47 chromosomes due to an extra c h r o m o s o m e #14 (Fig. 1) was found, w h i c h slowly increased from 60% to 80% of the cells in the bone marrow.
Figure 1
Hyperdiploid metaphase with 47 chromosomes due to an extra chromosome #14.
f
o
~t J ~
t~ t B
4
t
W O
\
Trisomy 14 in RAEB-t
317
DISCUSSION Primary karyotype abnormalities involving c h r o m o s o m e #14 are generally encountered in l y m p h o i d neoplasms. They consist of specific structural rearrangements that are closely related to and characteristic of disease entities of the B- and/or Tcell type. Trisomy 14 as the sole karyotype abnormality, on the other hand, is rare and so far has been d o c u m e n t e d in only four cases of hematologic malignancies [7], namely in one preleukemia [8], one Philadelphia-negative chronic myeloid leukemia [9], and two acute myeloid leukemias [10-12]. It also has been detected in two colonic polyps [13]. The leukemic patients' ages ranged from 40 to 87 years. Two protooncogenes, c-fos [14] and AKT1 [15], have been assigned to chromosome #14. c-fos is overexpressed in a variety of h u m a n neoplasms [16] and AKT-1 in gastrointestinal tumors [15]. Despite these findings, however, neither the normal biological function of these genes nor their specific i n v o l v e m e n t in any type of h u m an malignancy has yet been demonstrated. In conclusion, we suggest that trisomy 14 is another example of a rare but specific primary karyotype change in elderly patients, w h i c h apparently is exclusively connected with the m y e l o i d cell lineage. Supported in part by grants from the "Wissenschaftliche Fonds des Bfirgermeisters der Stadt Wien" and from the "Bundesministerium ffir Wissenschaft und Forschung, Wien, Austria". The authors thank Gertrude Ferstl for excellent technical assistance and Jean E. Haas-Makumbi for editing the manuscript. Dr. Haas is a recipient of a scholarship from the Max Kade Foundation.
REFERENCES 1. Heim S, Mittelman F (1986): Numerical chromosome aberrations in human neoplasia. Cancer Genet Cytogenet 22:99-108. 2. Mecucci C, Van Orshoven A, Tricot G, Michaux JL, Delannoy A, Van den Berghe H (1986): Trisomy 4 identifies a subset of acute nonlymphocytic leukemias. Blood 67:1328-1332. 3. Najfeld V, Seremetis S, Troy K, Uehlinger J, Schwartz P, Cuttner J (1986): Trisomy 22--A new abnormality found in acute leukemia characterized by eosinophilia and monocytoid blasts expressing immature differentiation antigens. Cancer Genet Cytogenet 23:105-114. 4. Sandberg AA, Morgan R, Sait SN, Berger R, Flandrin G, Schrier S, Hecht F (1987): Trisomy 4: An entity within acute non-lymphocytic leukemia. Cancer Genet Cytogenet 26:117-125. 5. Benett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C, The French-American-British (FAB) Co-operative Group (1981): Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189-199. 6. Haas OA, Schwarzmeier JD, Nacheva E, Fischer P, Paietta E (1984): Investigations on karyotype evolution in patients with chronic myeloid leukemia (CML). Blut 48:33-43. 7. Mitelman F (1985): Catalogue of chromosome aberrations in cancer. Progress and Topics in Cytogenetics, Vol. 5. Alan R, Liss. NY. 8. Nowell P, Finan J (1978): Chromosome studies in preleukemic states. IV. Myeloproliferatire versus cytopenic disorders. Cancer 42:2254-2261. 9. Shashaty GG, Baumiller RC (1980): Philadelphia chromosome-negative chronic myelogenous leukemia with Trisomy D. Arch Pathol Lab Med 104:376-378. 10. Li YS, Khalid G, Hayhoe FGJ (1983): Correlation between chromosomal pattern, cytological subtypes, response to therapy, and survival in acute myeloid leukaemia. Scand J Haematol 30:265-277. 11. Li YS, Matthews JG, Hayhoe FGJ (1984): A further study on quicker re-entry of chromosomally abnormal cells to active proliferation and preferential death of chromosomally normal cells during ageing of specimens in acute myeloid leukaemia (AML). Leuk Res 8:659-666.
318
o . A . Haas et al.
12. Yunis JJ (1984): Recurrent chromosomal defects are found in most patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 11:125-137. 13. Mitelman F, Mark J, Nilsson PG, Dencker H, Norryd C, Tranberg KG (1974): Chromosome banding pattern in human colonic polyps. Hereditas 78:63-68. 14. Barker PE, Rabin M, Watson M, Breg WR, Ruddle FH, Verma IM (1984): Human c-fos oncogene mapped within chromosomal region 14q21-q31. Proc Natl Acad Sci USA 81:5826-5830. 15. Testa JR, Huebner K, Croce CM, Staal S (1985): The AKT1 gene, the human homologue of a retroviral oncogene, is located on chromosome 14 at band q32. In: Human Gene Mapping, A. de la Chapelle, ed., Helsinki Conference, Eighth International Workshop on Human Gene Mapping, 1985, S. Karger, Basel, 761. 16. Slamon DJ, de Kernion JB, Verma IM, Cline MJ (1984): Expression of cellular oncogenes in human malignancies. Science 224:256-262.
ABSTRACT: Trisomy 14 was demonstrated on four occasions over a 2-year period in the bone marrow cells of a 63-year-old patient with refractory anemia with excess of blasts in transformation (RAEB-t). Trisomy 14 as the sole karyotype abnormality has been documented in only six malignancies, namely, in two cases of acute leukemias, one Philadelphia-negative chronic myeloid leukemia, one pancytopenia, and in two colonic polyps. In hematologic neoplasms, this rare primary change preferentially occurs in elderly adults and seems exclusively associated with the myeloid cell lineage.
INTRODUCTION The gain of one chromosome as the sole cytogenetic change has been reported in 6%-7% of all h u m a n neoplasms [1]. Chromosomes most often affected are #8, #9, #12, and #21. The frequency of such simple trisomies varies widely w i t h i n different neoplasms, but particular chromosomes are significantly associated with specific disease entities [1]. Trisomy 8, for example, is particularly common within a variety of myeloid neoplasias. Trisomy 4 and 22, on the other hand, are rather rare and their distinct connection with certain morphologic subgroups of acute myeloid leukemia has only been recognized recently [2-4]. We report herein the occurrence of trisomy 14 in a case of preleukemia that seems to be another rare but specific karyotype abnormality of myeloid disorders. CASE REPORT A 61-year-old m a n with a 3-month history of normochromic anemia was referred to the First Medical University Clinic, Vienna, for further diagnostic evaluation and treatment. With the exception of diabetes mellitus, arterial occlusion symptoms, and angina pectoris, his personal and family medical history was unremarkable. On admission his RBC was 2.3 x 1012/L, hemoglobin 100 g/L, WBC 2.6 x 109/L with 2% band forms, 38% segmented neutrophils, 2% eosinophils, 48% lymphocytes; platelets 61 × 109/L. No ringed sideroblasts were observed. Neither hepatospleno-
From the Departmentof Geneticsand Endocrinology,RoswellPark MemorialInstitute, Buffalo,NY (O. A. H.), the First Medical Clinic, Universityof Vienna (U. J., I. P.), and the St. Anna Children's Hospital (O. A. H., P. A.) Vienna,Austria. Address requests for reprints to Dr. Oskar A. Haas, St. A n n a Children's Hospital, Kinderspitalgasse 6, A-1090 Vienna, Austria. Received March 18, 1987; accepted April 28, 1987.
315 © 1987 Elsevier SciencePublishingCo., Inc. 52 VanderbiltAve., New York, NY 10017
Cancer Genet Cytogenet29:315-318(1987) 0165-4608/87/$03.50
316
O . A . Haas et al. megaly nor l y m p h a d e n o p a t h y was evident. Bone marrow aspirate and b i o p s y showed h y p e r c e l l u l a r i t y with dyserythro-, dysgranulo-, and dysmegakaryocytopoiesis and 10% m y e l o i d blasts in w h i c h occasional Auer rods were present. According to the criteria of the FAB classification [5], refractory anemia with excess of blasts in transformation (RAEB-t) was diagnosed. Within the following months the patient was transfused with RBC and platelet concentrates w h e n e v e r necessary. Two months after diagnosis, therapy with low-dose c y t o s i n e - a r a b i n o s i d e was initiated and repeated 6 months later. It lead to only a slight reduction of the blast cells, but to a partial remission of the peripheral red blood cell and platelet count. Two years after diagnosis the patient remains in stable condition.
CYTOGENETIC STUDIES
Chromosome analyses were performed on bone marrow short-term cultures 6, 12, 22, and 26 months after diagnosis. The samples were cultured for 24 hours, processed according to standard cytogenetic techniques, and stained with t r y p s i n Giemsa as previously described [6]. At least 20 metaphases were karyotyped on each occasion. In a d d i t i o n to normal male metaphases, a h y p e r d i p l o i d clone with 47 chromosomes due to an extra c h r o m o s o m e #14 (Fig. 1) was found, w h i c h slowly increased from 60% to 80% of the cells in the bone marrow.
Figure 1
Hyperdiploid metaphase with 47 chromosomes due to an extra chromosome #14.
f
o
~t J ~
t~ t B
4
t
W O
\
Trisomy 14 in RAEB-t
317
DISCUSSION Primary karyotype abnormalities involving c h r o m o s o m e #14 are generally encountered in l y m p h o i d neoplasms. They consist of specific structural rearrangements that are closely related to and characteristic of disease entities of the B- and/or Tcell type. Trisomy 14 as the sole karyotype abnormality, on the other hand, is rare and so far has been d o c u m e n t e d in only four cases of hematologic malignancies [7], namely in one preleukemia [8], one Philadelphia-negative chronic myeloid leukemia [9], and two acute myeloid leukemias [10-12]. It also has been detected in two colonic polyps [13]. The leukemic patients' ages ranged from 40 to 87 years. Two protooncogenes, c-fos [14] and AKT1 [15], have been assigned to chromosome #14. c-fos is overexpressed in a variety of h u m a n neoplasms [16] and AKT-1 in gastrointestinal tumors [15]. Despite these findings, however, neither the normal biological function of these genes nor their specific i n v o l v e m e n t in any type of h u m an malignancy has yet been demonstrated. In conclusion, we suggest that trisomy 14 is another example of a rare but specific primary karyotype change in elderly patients, w h i c h apparently is exclusively connected with the m y e l o i d cell lineage. Supported in part by grants from the "Wissenschaftliche Fonds des Bfirgermeisters der Stadt Wien" and from the "Bundesministerium ffir Wissenschaft und Forschung, Wien, Austria". The authors thank Gertrude Ferstl for excellent technical assistance and Jean E. Haas-Makumbi for editing the manuscript. Dr. Haas is a recipient of a scholarship from the Max Kade Foundation.
REFERENCES 1. Heim S, Mittelman F (1986): Numerical chromosome aberrations in human neoplasia. Cancer Genet Cytogenet 22:99-108. 2. Mecucci C, Van Orshoven A, Tricot G, Michaux JL, Delannoy A, Van den Berghe H (1986): Trisomy 4 identifies a subset of acute nonlymphocytic leukemias. Blood 67:1328-1332. 3. Najfeld V, Seremetis S, Troy K, Uehlinger J, Schwartz P, Cuttner J (1986): Trisomy 22--A new abnormality found in acute leukemia characterized by eosinophilia and monocytoid blasts expressing immature differentiation antigens. Cancer Genet Cytogenet 23:105-114. 4. Sandberg AA, Morgan R, Sait SN, Berger R, Flandrin G, Schrier S, Hecht F (1987): Trisomy 4: An entity within acute non-lymphocytic leukemia. Cancer Genet Cytogenet 26:117-125. 5. Benett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C, The French-American-British (FAB) Co-operative Group (1981): Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189-199. 6. Haas OA, Schwarzmeier JD, Nacheva E, Fischer P, Paietta E (1984): Investigations on karyotype evolution in patients with chronic myeloid leukemia (CML). Blut 48:33-43. 7. Mitelman F (1985): Catalogue of chromosome aberrations in cancer. Progress and Topics in Cytogenetics, Vol. 5. Alan R, Liss. NY. 8. Nowell P, Finan J (1978): Chromosome studies in preleukemic states. IV. Myeloproliferatire versus cytopenic disorders. Cancer 42:2254-2261. 9. Shashaty GG, Baumiller RC (1980): Philadelphia chromosome-negative chronic myelogenous leukemia with Trisomy D. Arch Pathol Lab Med 104:376-378. 10. Li YS, Khalid G, Hayhoe FGJ (1983): Correlation between chromosomal pattern, cytological subtypes, response to therapy, and survival in acute myeloid leukaemia. Scand J Haematol 30:265-277. 11. Li YS, Matthews JG, Hayhoe FGJ (1984): A further study on quicker re-entry of chromosomally abnormal cells to active proliferation and preferential death of chromosomally normal cells during ageing of specimens in acute myeloid leukaemia (AML). Leuk Res 8:659-666.
318
o . A . Haas et al.
12. Yunis JJ (1984): Recurrent chromosomal defects are found in most patients with acute nonlymphocytic leukemia. Cancer Genet Cytogenet 11:125-137. 13. Mitelman F, Mark J, Nilsson PG, Dencker H, Norryd C, Tranberg KG (1974): Chromosome banding pattern in human colonic polyps. Hereditas 78:63-68. 14. Barker PE, Rabin M, Watson M, Breg WR, Ruddle FH, Verma IM (1984): Human c-fos oncogene mapped within chromosomal region 14q21-q31. Proc Natl Acad Sci USA 81:5826-5830. 15. Testa JR, Huebner K, Croce CM, Staal S (1985): The AKT1 gene, the human homologue of a retroviral oncogene, is located on chromosome 14 at band q32. In: Human Gene Mapping, A. de la Chapelle, ed., Helsinki Conference, Eighth International Workshop on Human Gene Mapping, 1985, S. Karger, Basel, 761. 16. Slamon DJ, de Kernion JB, Verma IM, Cline MJ (1984): Expression of cellular oncogenes in human malignancies. Science 224:256-262.