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Clinical significance of isolated del(7p) in myeloid neoplasms
Leukemia Research 55 (2017) 18–22
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Clinical significance of isolated del(7p) in myeloid neoplasms Hatice Deniz Gur, Sa A. Wang, Zhenya Tang, Shimin Hu, Shaoying Li, L. Jeffrey Medeiros, Guilin Tang ∗ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
a r t i c l e
i n f o
Article history: Received 11 December 2016 Received in revised form 5 January 2017 Accepted 9 January 2017 Available online 16 January 2017 Keywords: Del(7p) Myeloid neoplasms Disease progression Refractory to therapy
a b s t r a c t Sole del(7p) is a rare finding in myeloid neoplasms and its clinical significance is largely unknown. Here we report 10 patients with isolated del(7p), 4 had acute myeloid leukemia (AML), 2 myelodysplastic syndromes (MDS), 1 chronic myelomonocytic leukemia (CMML), 1 primary myelofibrosis (PMF), and 2 AML in remission. Seven patients had large and 3 had small del(7p) clone. For patients with AML, 3 acquired del(7p) either at disease relapse or disease progression, then became refractory to therapy and died shortly thereafter (median 5 months). Detection of del(7p) in patients with MDS, CMML, or PMF appeared to predict poorer prognosis as all 4 patients experienced disease progression or transformation to AML after 5–24 months. In the remaining 3 patients (1 AML and 2 AML in remission), del(7p) was only detected in 10% to 30% of metaphases and was a transient finding that did not appear to have any clinical impact. We conclude that detection of del(7p) in myeloid neoplasms, when presents as a major clone, often poses a high risk for disease progression and refractoriness to therapy; whereas when del(7p) presents as a small clone, it may not carry any clinical significance. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction Abnormalities of chromosome 7, either the loss of a whole chromosome 7 (monosomy 7, −7) or deletion (del) of the long arm (7q), are common in myeloid neoplasms (MNs), occurring in 8–10% of de novo myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [1–3], and 40–50% of therapy-related MDS/AML (t-MDS/AML) [4]. Recently, studies have shown that −7 in MDS is associated with an unfavorable overall survival (OS) and higher risk of AML transformation as compared with del(7q) [5]. Del(7q) is therefore considered as an intermediate risk whereas −7 as a high or poor risk in patients with MDS [1,2] or AML [6]. In children with B-cell precursor lymphoblastic leukemia (BCP-ALL), it has been shown that deletion of short arm of chromosome 7 [del(7p)], similar to −7, conferred an inferior outcome independent of other prognostic factors [7]. These findings suggest that the genes located in the short arm (7p) may contribute to the pathogenesis and biological behavior of myeloid neoplasms. In contrast to del(7q)/-7 which are common in myeloid neoplasms, isolated del(7p) is very rare. To our knowledge, there have
∗ Corresponding author at: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 151 Holcombe Boulevard, Houston, TX 770304009, USA. E-mail address: [email protected] (G. Tang). http://dx.doi.org/10.1016/j.leukres.2017.01.016 0145-2126/© 2017 Elsevier Ltd. All rights reserved.
been no studies focused on the characteristics of patients with MNs associated with del(7p). In this study, we searched our database for all cases with del(7p) as a sole abnormality, and identified 10 patients who had MNs or a history of MNs. We summarized the clinical, pathological and cytogenetic features of these patients. 2. Materials and methods 2.1. Patients We searched the Clinical Cytogenetics Laboratory at The University of Texas MD Anderson Cancer Center from January 2004 through December 2015 for cases of isolated del(7p). Clinical data, response to treatment and patient outcomes were obtained by a retrospective review of medical records. All samples were collected following institutional guidelines with informed consent in accordance with the Declaration of Helsinki. 2.2. Laboratory data and morphological examination Peripheral blood (PB) smears, bone marrow (BM) aspirate smears, and trephine biopsy specimens were reviewed in all cases. Blast morphology and percentage, BM cellularity, and background dysplasia were assessed. Laboratory data including leukocyte count, hemoglobin level, platelet count, and blast count were collected.
H.D. Gur et al. / Leukemia Research 55 (2017) 18–22
2.3. Conventional karyotyping Chromosomal analysis was performed on G-banded metaphase cells prepared from 24-h and 48-h bone marrow aspirate cultured cells. Twenty metaphases were analyzed and the results were reported using the International System for Human Cytogenetic Nomenclature (2016) [8]. Del(7p) clone size was arbitrarily defined as large (present in ≥50% of metaphases) or small (present in <50% metaphases). 3. Results 3.1. Patients A total of 11 patients with isolated del(7p) were identified over a 12 year time period, 10 with myeloid neoplasms (∼0.05% of all MNs) and 1 with BCP-ALL. The patients with myeloid neoplasms are the focus of this study and the clinical information for these 10 patients is summarized in Table 1. There were 6 women and 4 men, with a median age of 53 years (range; 41–68). Three patients (cases #1-3) had del(7p) detected at the time of diagnosis; Patient #4, #5, #10 had a history of AML with maturation with a normal diploid karyotype, and had been treated with 3 + 7 induction chemotherapy. Patient #6 had a history of splenic marginal zone lymphoma and had been treated with FCR regimen (Fludarabine, cyclophosphamide, rituximab) for 8 cycles; Patient #7 had a history of AML with t(8;21)(q22;q22) and was treated with cyclophosphamide, cytarabine, and topotecan; Patient #8 had a history of breast cancer and was treated with lumpectomy, chemotherapy (Adriamycin, Taxol) and radiotherapy; Patient #9 had a history of AML with maturation with unknown karyotype was treated with 3 + 7 induction followed by allogeneic stem cell transplant. At the time of del(7p) detection, 4 patients had AML, including 1 (case #3) acute monoblastic leukemia, 2 (cases #4 and 5)AML in relapse, 1 (case #6) AML with myelodysplasia-related changes; 2 patients had therapy-related MDS, case #7 with excess blasts and case #8 with multilineage dysplasia; 1 (case #1) with CMML-1; 1 (case #2) with PMF; and 2 negative BM (AML in remission) (Table 1). The bone marrow and peripheral blood findings were summarized in Supplementary table. 3.2. Cytogenetic findings and clinical correlations The cytogenetic information was summarized in Table 2. At the time of del(7p) detection, 4 cases (cases #2, 3, 6, 9) showed terminal 7p deletion and the other 6 had interstitial 7p deletion (Fig. 1A–E). 7p15 was the most common break point and was deleted in all cases. Seven (cases #1–2, 4–8) patients had del(7p) detected in the majority of the metaphases (80–100%, median 100%) and 3 patients (cases #3, 9–10) had del(7p) detected in 2 (10%), 5 (25%) or 6 (30%) of 20 metaphases. Of the 7 patients in whom del(7p) was a large clone, patient #1 was initially diagnosed with CMML-1 with del(7p), and progressed to AML after 18 months and died 3 months later. Patient #2 was initially diagnosed with PMF with del(7p), progressed to AML after 2 years, treated with induction chemotherapy and hematopoietic stem cell transplant (HSCT). The patient was in remission with a normal karyotype and alive at the last follow-up. Patient #4 had a history of AML with a normal karyotype and del(7p) was detected at relapse 6 months after remission. Del(7p) was persistently detected in the follow-up BM with refractory AML, and later an additional new unrelated clone emerged 46,XX,del(7)(p15p21) [18]/46,XX,t(8;13)(p23;q14),add(16)(q24) [2], patient died after 8 months since del(7p) detection. Patient
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#5 had a history of AML with a normal diploid karyotype and del(7p) was detected at AML relapse after 30 months in remission. The patient responded initially to therapies with clearance of del(7p), but relapsed soon after with reappearance of del(7p). Patient died after 18 months since del(7p) detection Patient #6 had a history of splenic marginal zone lymphoma which was treated with FCR, he developed t-MDS 76 months later with an abnormal karyotype of 47,XX,+8[5]/46,XX[15]. Thirteen months later, the patient experienced AML (with myelodysplasiarelated changes) progression, at this time +8 was no longer detected and del(7p) emerged. Patient died of AML at 0.3 month after del(7p) detection. Patient #7 had a history of AML with t(8;21) who was successfully treated and achieved clinical, morphological and cytogenetic remission for 7 years. He then developed t-MDS (MDS with excess blasts) with del(7p), and 21 months later, progressed to AML (with myelodysplasiarelated changes) with clonal evolution and the karyotype showed 46,XX,del(7)(p15p22)[3]/49,XX,del(7)(p15p22),+8,+12,+21[17]. She died of AML 4 months later. Patient #8 had a history of breast cancer treated with chemotherapy and radiotherapy. The baseline karyotype was unknown. She developed t-MDS (MDS with multilineage dysplasia) 108 months later with detection of del(7p), and progressed to CMML-2 after 5 months. Patient died of disease 1 month later. Overall, the presence of a large del(7p) clone correlated well with disease status in these 7 patients. Three patients had del(7p) as a small clone. Patient #3 had del(7p) detected at the time of initial diagnosis of AML that was refractory to therapies, del(7p) was detected in the first 2 BM samples in 2/20 metaphases; however, the next 2 BM samples yielded insufficient metaphases (5 and 1, respectively) without del(7p) detection. Patient #9 and #10 had a similar clinical course, both had a history of AML and del(7p) was detected when both patients were in clinical and morphological remission. Del(7p) was persistently detected as a small clone in BM samples for 12–27 months and then disappeared. These 2 patients had unremarkable BM morphologic findings and had a normal complete blood count in all follow-up BM/PB samples. Both patients were alive and remained in remission at last clinical follow-up. 3.3. Molecular findings Patients were tested for a variety of gene mutations determined by disease type and protocols active at the time. The genes tested (Table 2) included NRAS (n = 6), KRAS (n = 6), NPM1 (n = 5), FLT3 (n = 5), CEBPA (n = 3), KIT (n = 2), and JAK2 (n = 2). Case #3 had NRAS mutation detected at the initial diagnosis of AML, the same time when a small clone of del(7p) was detected; case #4 and #5 had FLT3-ITD and NPM1 mutation detected at the initial diagnosis of AML, and these two mutations were detected again at AML relapse when del(7p) was detected; gene mutations were not detected in other cases. 4. Discussion Del(7p) as a sole abnormality is very rare, mainly detected in patients with myeloid neoplasms, including AML, MDS, CMML to PMF in this cohort, and presenting either as de novo, therapyrelated or relapsed disease. In this study, we present evidence that a large clone (>50% of metaphases) of del(7q) appears to be a high risk cytogenetic abnormality associated with progression or relapse of disease. However, del(7p) can also be seen as “clonal cytogenetic abnormality of uncertain significance” if they are only detected in a low number of metaphases. There were 4 patients with AML with isolated del(7p) in this study. One patient (#3) had del(7p) at the time of diagnosis. In
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H.D. Gur et al. / Leukemia Research 55 (2017) 18–22
Table 1 Demographic and clinical information. Case#
Age/Sex
Prior diagnosis
Prior therapy
Interval (Mon)
BM Diagnosis
Therapies after del(7p)
Follow-up
OS (mon)/Outcome
1
63/M
No
No
0
CMML
To AML
21/DOD
2
53/M
No
No
0
PMF
To AML
95* /ACR
3
66/F
No
No
0
AML-M5a
Refractory AML
2/DOD
4
60/F
AML-M2
Chemotherapy (induction 3 + 7)
7
Relapsed AML
Refractory AML
8/DOD
5
60/F
AML-M2
Relapsed AML
Refractory AML
18/DOD
6 7
47/F 49/F
Splenic MZL AML with t(8;21)
Chemotherapy 30 (induction 3 + 7) FCRx8 76 cyclophosphamide,88 ara-C, topotecan
Refractory AML To AML
0.3/DOD 25/DOD
8
68/F
Breast cancer
108
t-MDS
To CMML-2
6* /DOD
9
41/M
AML-M2
15
Negative BM
Observation
In remission
35/ACR
10
50/M
AML-M2
Adriamycin, Taxol Radiotherapy Chemotherapy (induction 3 + 7), SCT Chemotherapy (induction 3 + 7)
Idarubicin, cytarabine Fludarabine + busulfan Plerixafor + clofarabine,Ruxolitinib Plerixafor + Cytarabine + Daunorubicin, Vidaza Voreloxin + Cytarabine, Plerixafor Decitabine Decidabin, Filanesib, Mylotarg, Vidaza Decitabine
12
Negative BM
Observation
In remission
107/ACR
AML-MRC t-MDS
Interval: from the initiation of cytotoxic therapy to the detection of del(7p). OS: overall survival, from the date of del(7p) detection to the date of death or last follow-up for alive patients. ACR: alive with complete remission; AML: acute myeloid leukemia; AML-M2: acute myeloid leukemia with maturation; AML-M5a: acute monoblastic leukemia; AML-MRC: acute myeloid leukemia with myelodysplasia-related changes; BM: bone marrow; CMML: chronic myelomonocytic leukemia; DOD: died of disease; F: female; FCR x 8: Fludarabine, cyclophosphamide, rituximab for 8 cycles; M: male; MDS: myelodysplastic syndromes; MZL: marginal zone lymphoma; PMF: Primary myelofibrosis; SCT: stem cell transplant; t-: therapy-related. * Received allogeneic stem cell transplant. Table 2 Cytogenetic and molecular information. Case# Prior karyotype
Del(7p) clone*
CG FU Del(7p) outcome
1 2 3 4 5 6 7 8 9 10
46,XY,del(7)(p13p15)[18] 46,XY,del(7)(p15)[20] 46,XX,del(7)(p12)[2] 46,XX,del(7)(p15p21) [20] 46,XX,del(7)(p15p21)[16] 46,XX,del(7)(p12)[20] 46,XX,del(7)(p15p22)[20] 46,XX,del(7)(p15p22)[20] 46,XY,del(7)(p15)[5] 46,XY,del(7)(p15p22)[6]
8x 9x 3x 5x 4x none 4x 5x 8x 5x
No No No 46,XX[20] 46,XX[20] 47,XX,+8 [5]/46,XX[15] 45,X,-X,t(8;21) (q22;q22)[16] Unknown Unknown 46,XY[20]
Persistent Persistent** persistent Persistent, + new clone Persistent NA Clonal evolution Persistent Disappeared after 12 m Disappeared after 27 m
Gene mutation tested Mutated
Unmutated
None None NRAS FLT3-ITD, NPM1 FLT3-ITD, NPM1 N/A None None None None
NRAS, KRAS, FLT3 JAK2 KRAS, NPM1, CEBPA, IDH1/2, KIT KRAS, NRAS, IDH1/2, CEBPA, JAK2 KRAS, NRAS, KIT N/A FLT3, NPM1 FLT3, NPM1, KRAS, NRAS, IDH1/2, DNMT3A, CEBPA FLT3 KRAS, NRAS, FLT3
CG: cytogenetics; FU: follow-up; NA: not applicable. * A total of 20 metaphases were analyzed, only the clone with del(7p) was listed here, the remaining metaphases showed a normal diploid karyotype. ** Disappeared after stem cell transplant.
this patient, del(7p) was detected in 2/20 metaphases and then became undetectable during the course of disease, suggesting that del(7p) might not be directly associated with AML pathogenesis. In contrast, the other 3 AML patients were found to have isolated del(7p) either at disease relapse or when MDS progressed to AML. The acquisition of del(7p) in these 3 patients was associated with refractoriness to therapy and short survival (range, 0.3–18 months). These findings suggest that in AML, isolated del(7p) likely presents as an acquired clonal cytogenetic abnormality, closely related to disease progression or relapse, and may be associated with a poor outcome. In contrast to AML, in 4 patients who presented with t-MDS, CMML or PMF, sole del(7p) was detected at the time of
diagnosis. All 4 patients had a large and persistent del(7p) clone, and all patients showed disease progression and/or transformed to AML within 2 years. Except for 1 patient (case #2) who received HSCT, the other 3 patients died shortly after disease progression. Although the number of patients was small and there were other confounding factors, a major clone of del(7p) appeared to be a cytogenetic abnormality associated with a high risk of progression and a poor patient outcome. We reported previously that in the post chemotherapy setting, some clonal cytogenetic abnormalities, including del(7q), can be clinically “silent” or appear to be without clinical significance [9,10]. These types of cytogenetic abnormalities often present in isolation,
H.D. Gur et al. / Leukemia Research 55 (2017) 18–22
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Fig. 1. Chromosome analysis showed del(7p) at different breakpoints. (A) karyotype of case #2: 46,XY,del(7)(p15); (B) case #1: del(7)(p13p15); (C) case #4: del(7)(p15p21); (D) case #6: del(7)(p12); (E) case #7: del(7)(p15p22).
involve a small number of metaphases, and may or may not be persistent in follow-up BMs. Similarly, small clone of del(7p), if it emerges in patients who have received prior cytotoxic therapies, presented as a sole abnormality and involves a small number of metaphases, does not seem to be disease-associated. This was evident in 2 patients (cases #9-10) who received chemotherapies for AML and achieved complete remission, but 12–15 months later, the patients were found to have a small del(7p) clone in their BMs. In both patients, del(7p) was repeatedly detected in BM for 12–27 months, but eventually became undetectable. Both patients remained in remission and showed no evidence of secondary myeloid neoplasms during the follow-up period (up to 107 months). These observations indicate that not all del(7p) are disease-associated, especially while it presents as a small clone. It is worth to mention that the clone size could be more precisely estimated by interphase fluorescence in situ hybridization (FISH), especially in patients #3, 9 and 10 with low numbers of metaphases. However, due to no archived materials, FISH was not performed in this study. Based on our previous studies [10–12], the clone size determined by metaphases is often larger but proportionally correlated with the clone size detected by interphase FISH. Studies have confirmed that MDS/AML patients with complete loss of chromosome 7 (-7) have a much poorer outcome compared with patients who have del(7q). These results suggest that
there are critical genetic materials located on chromosome 7p that might contribute to the poor outcomes of patients with MDS/AML. Although no gene has been identified on 7p that appears to be associated with myeloid neoplasms and poor outcome, there are several putative genes on 7p that may be associated with hematopoietic malignancies. One of the genes is in the IKAROS family zinc finger 1 (IK2F1) located on 7p12. IK2F1 is a transcription factors involved in chromatin remodeling and plays a key role in hematopoietic stem cell maintenance, and B- and T- cell lymphopoiesis. IKZF1 and ETV6 are components of a network of heptad transcription factors that regulate genes in hematopoietic stem and progenitor cells, dysregulation of these genes in AML is associated with poor prognosis [13]; Others also have shown that deletion of IKZF1 is associated with unfavorable prognosis in childhood BCP-ALL [14] and a higher relapse risk and worse survival in adults with common BCP-ALL [15]. Recent studies also suggested that IKZF1 was involved in myeloid differentiation and might have a role in oncogenesis of pediatric AML with loss of chromosome 7 [16]. Another putative gene, ubiquitin-specific protease gene (UPS 42), located on 7p22, might play a pathogenetic role in MDS and AML through chromosome rearrangement [17,18]. Nonetheless, the genetic mechanisms underlying this abnormality are largely unknown and require further investigation. Unfortunately, no remaining BM sample was available to enable us to do further studies (such as array compar-
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H.D. Gur et al. / Leukemia Research 55 (2017) 18–22
ative genomic hybridization, aCGH), to narrow down the critical regions in 7p. In conclusion, del(7p) as a sole abnormality can be rarely detected in bone marrows of patients with a variety of myeloid neoplasms. When present as a large clone, isolated del(7p) appears to be associated with a high risk for disease progression, refractoriness to therapy and an inferior outcome. On the other hand, when del(7p) only involves a small number of metaphases, it can be a transient finding that poses no clinical consequence. We suggest these findings also emphasize a more general principle that the size of cytogenetic clone, as well as a specific chromosomal abnormality, is important information to consider in the risk assessment of patients with myeloid neoplasms. Acknowledgements The authors would like to thank colleagues from department of hematopathology and clinical cytogenetic laboratory for their great inputs. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.leukres.2017. 01.016. References [1] P.L. Greenberg, H. Tuechler, J. Schanz, G. Sanz, G. Garcia-Manero, F. Sole, et al., Revised international prognostic scoring system for myelodysplastic syndromes, Blood 120 (12) (2012) 2454–2465. [2] J. Schanz, H. Tuchler, F. Sole, M. Mallo, E. Luno, J. Cervera, et al., New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge, J. Clin. Oncol. 30 (8) (2012) 820–829. [3] O. Pozdnyakova, P.M. Miron, G. Tang, O. Walter, A. Raza, B. Woda, et al., Cytogenetic abnormalities in a series of 1,029 patients with primary myelodysplastic syndromes: a report from the US with a focus on some undefined single chromosomal abnormalities, Cancer 113 (12) (2008) 3331–3340. [4] S.H. Swerdlow, C. Campo, N.L. Harris, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Edited by International Agency for Research on Cancer, The International Agency for Research on Cancer, Lyon, 2008.
[5] I. Cordoba, J.R. Gonzalez-Porras, B. Nomdedeu, E. Luno, R. de Paz, E. Such, et al., Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome, Cancer 118 (1) (2012) 127–133. [6] H. Dohner, E.H. Estey, S. Amadori, F.R. Appelbaum, T. Buchner, A.K. Burnett, et al., Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet, Blood 115 (3) (2010) 453–474. [7] N.A. Heerema, J.B. Nachman, H.N. Sather, M.K. La, R. Hutchinson, B.J. Lange, et al., Deletion of 7p or monosomy 7 in pediatric acute lymphoblastic leukemia is an adverse prognostic factor: a report from the Children’s Cancer Group, Leukemia 18 (5) (2004) 939–947. [8] L.G. Shaffer, J. McGowan-Jordan, M. Schmid, An International System for Human Cytogenetic Nomenclature, S. Karger Basel, 2016. [9] G. Tang, S.A. Wang, V. Lu, H.C. Lee, M.H. Qazilbash, X.I. Wang, et al., Clinically silent clonal cytogenetic abnormalities arising in patients treated for lymphoid neoplasms, Leuk. Res. 38 (8) (2014) 896–900. [10] R.S. Goswami, S.A. Wang, C. DiNardo, Z. Tang, Y. Li, W. Zuo, et al., Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms, Mod. Pathol. 29 (7) (2016) 727–734. [11] C.C. Yin, J. Peng, Y. Li, R.K. Shamanna, T. Muzzafar, C. DiNardo, et al., Clinical significance of newly emerged isolated del(20q) in patients following cytotoxic therapies, Mod. Pathol. 29 (8) (2016) 939. [12] G. Tang, R.S. Goswami, C.S. Liang, C.E. Bueso-Ramos, S. Hu, C. DiNardo, et al., Isolated del(5q) in patients following therapies for various malignancies may not all Be clinically significant, Am. J. Clin. Pathol. 144 (1) (2015) 78–86. [13] A. Unnikrishnan, Y.F. Guan, Y. Huang, D. Beck, J.A. Thoms, S. Peirs, et al., A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network, Nucl. Acids Res. (2016), Epub ahead of print. [14] J.M. Boer, A. van der Veer, D. Rizopoulos, M. Fiocco, E. Sonneveld, H.A. de Groot-Kruseman, et al., Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study, Leukemia 30 (1) (2016) 32–38. [15] Q.M. Yao, K.Y. Liu, R.P. Gale, B. Jiang, Y.R. Liu, Q. Jiang, et al., Prognostic impact of IKZF1 deletion in adults with common B-cell acute lymphoblastic leukemia, BMC Cancer 16 (2016) 269. [16] J.D. de Rooij, E. Beuling, M.M. van den Heuvel-Eibrink, A. Obulkasim, A. Baruchel, J. Trka, et al., Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia, Haematologica 100 (9) (2015) 1151–1159. [17] K. Paulsson, A.N. Bekassy, T. Olofsson, F. Mitelman, B. Johansson, I. Panagopoulos, A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42, Leukemia 20 (2) (2006) 224–229. [18] N. Foster, K. Paulsson, M. Sales, J. Cunningham, M. Groves, N. O’Connor, et al., Molecular characterisation of a recurrent, semi-cryptic RUNX1 translocation t(7;21) in myelodysplastic syndrome and acute myeloid leukaemia, Br. J. Haematol. 148 (6) (2010) 938–943.
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Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Clinical significance of isolated del(7p) in myeloid neoplasms Hatice Deniz Gur, Sa A. Wang, Zhenya Tang, Shimin Hu, Shaoying Li, L. Jeffrey Medeiros, Guilin Tang ∗ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
a r t i c l e
i n f o
Article history: Received 11 December 2016 Received in revised form 5 January 2017 Accepted 9 January 2017 Available online 16 January 2017 Keywords: Del(7p) Myeloid neoplasms Disease progression Refractory to therapy
a b s t r a c t Sole del(7p) is a rare finding in myeloid neoplasms and its clinical significance is largely unknown. Here we report 10 patients with isolated del(7p), 4 had acute myeloid leukemia (AML), 2 myelodysplastic syndromes (MDS), 1 chronic myelomonocytic leukemia (CMML), 1 primary myelofibrosis (PMF), and 2 AML in remission. Seven patients had large and 3 had small del(7p) clone. For patients with AML, 3 acquired del(7p) either at disease relapse or disease progression, then became refractory to therapy and died shortly thereafter (median 5 months). Detection of del(7p) in patients with MDS, CMML, or PMF appeared to predict poorer prognosis as all 4 patients experienced disease progression or transformation to AML after 5–24 months. In the remaining 3 patients (1 AML and 2 AML in remission), del(7p) was only detected in 10% to 30% of metaphases and was a transient finding that did not appear to have any clinical impact. We conclude that detection of del(7p) in myeloid neoplasms, when presents as a major clone, often poses a high risk for disease progression and refractoriness to therapy; whereas when del(7p) presents as a small clone, it may not carry any clinical significance. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction Abnormalities of chromosome 7, either the loss of a whole chromosome 7 (monosomy 7, −7) or deletion (del) of the long arm (7q), are common in myeloid neoplasms (MNs), occurring in 8–10% of de novo myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [1–3], and 40–50% of therapy-related MDS/AML (t-MDS/AML) [4]. Recently, studies have shown that −7 in MDS is associated with an unfavorable overall survival (OS) and higher risk of AML transformation as compared with del(7q) [5]. Del(7q) is therefore considered as an intermediate risk whereas −7 as a high or poor risk in patients with MDS [1,2] or AML [6]. In children with B-cell precursor lymphoblastic leukemia (BCP-ALL), it has been shown that deletion of short arm of chromosome 7 [del(7p)], similar to −7, conferred an inferior outcome independent of other prognostic factors [7]. These findings suggest that the genes located in the short arm (7p) may contribute to the pathogenesis and biological behavior of myeloid neoplasms. In contrast to del(7q)/-7 which are common in myeloid neoplasms, isolated del(7p) is very rare. To our knowledge, there have
∗ Corresponding author at: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 151 Holcombe Boulevard, Houston, TX 770304009, USA. E-mail address: [email protected] (G. Tang). http://dx.doi.org/10.1016/j.leukres.2017.01.016 0145-2126/© 2017 Elsevier Ltd. All rights reserved.
been no studies focused on the characteristics of patients with MNs associated with del(7p). In this study, we searched our database for all cases with del(7p) as a sole abnormality, and identified 10 patients who had MNs or a history of MNs. We summarized the clinical, pathological and cytogenetic features of these patients. 2. Materials and methods 2.1. Patients We searched the Clinical Cytogenetics Laboratory at The University of Texas MD Anderson Cancer Center from January 2004 through December 2015 for cases of isolated del(7p). Clinical data, response to treatment and patient outcomes were obtained by a retrospective review of medical records. All samples were collected following institutional guidelines with informed consent in accordance with the Declaration of Helsinki. 2.2. Laboratory data and morphological examination Peripheral blood (PB) smears, bone marrow (BM) aspirate smears, and trephine biopsy specimens were reviewed in all cases. Blast morphology and percentage, BM cellularity, and background dysplasia were assessed. Laboratory data including leukocyte count, hemoglobin level, platelet count, and blast count were collected.
H.D. Gur et al. / Leukemia Research 55 (2017) 18–22
2.3. Conventional karyotyping Chromosomal analysis was performed on G-banded metaphase cells prepared from 24-h and 48-h bone marrow aspirate cultured cells. Twenty metaphases were analyzed and the results were reported using the International System for Human Cytogenetic Nomenclature (2016) [8]. Del(7p) clone size was arbitrarily defined as large (present in ≥50% of metaphases) or small (present in <50% metaphases). 3. Results 3.1. Patients A total of 11 patients with isolated del(7p) were identified over a 12 year time period, 10 with myeloid neoplasms (∼0.05% of all MNs) and 1 with BCP-ALL. The patients with myeloid neoplasms are the focus of this study and the clinical information for these 10 patients is summarized in Table 1. There were 6 women and 4 men, with a median age of 53 years (range; 41–68). Three patients (cases #1-3) had del(7p) detected at the time of diagnosis; Patient #4, #5, #10 had a history of AML with maturation with a normal diploid karyotype, and had been treated with 3 + 7 induction chemotherapy. Patient #6 had a history of splenic marginal zone lymphoma and had been treated with FCR regimen (Fludarabine, cyclophosphamide, rituximab) for 8 cycles; Patient #7 had a history of AML with t(8;21)(q22;q22) and was treated with cyclophosphamide, cytarabine, and topotecan; Patient #8 had a history of breast cancer and was treated with lumpectomy, chemotherapy (Adriamycin, Taxol) and radiotherapy; Patient #9 had a history of AML with maturation with unknown karyotype was treated with 3 + 7 induction followed by allogeneic stem cell transplant. At the time of del(7p) detection, 4 patients had AML, including 1 (case #3) acute monoblastic leukemia, 2 (cases #4 and 5)AML in relapse, 1 (case #6) AML with myelodysplasia-related changes; 2 patients had therapy-related MDS, case #7 with excess blasts and case #8 with multilineage dysplasia; 1 (case #1) with CMML-1; 1 (case #2) with PMF; and 2 negative BM (AML in remission) (Table 1). The bone marrow and peripheral blood findings were summarized in Supplementary table. 3.2. Cytogenetic findings and clinical correlations The cytogenetic information was summarized in Table 2. At the time of del(7p) detection, 4 cases (cases #2, 3, 6, 9) showed terminal 7p deletion and the other 6 had interstitial 7p deletion (Fig. 1A–E). 7p15 was the most common break point and was deleted in all cases. Seven (cases #1–2, 4–8) patients had del(7p) detected in the majority of the metaphases (80–100%, median 100%) and 3 patients (cases #3, 9–10) had del(7p) detected in 2 (10%), 5 (25%) or 6 (30%) of 20 metaphases. Of the 7 patients in whom del(7p) was a large clone, patient #1 was initially diagnosed with CMML-1 with del(7p), and progressed to AML after 18 months and died 3 months later. Patient #2 was initially diagnosed with PMF with del(7p), progressed to AML after 2 years, treated with induction chemotherapy and hematopoietic stem cell transplant (HSCT). The patient was in remission with a normal karyotype and alive at the last follow-up. Patient #4 had a history of AML with a normal karyotype and del(7p) was detected at relapse 6 months after remission. Del(7p) was persistently detected in the follow-up BM with refractory AML, and later an additional new unrelated clone emerged 46,XX,del(7)(p15p21) [18]/46,XX,t(8;13)(p23;q14),add(16)(q24) [2], patient died after 8 months since del(7p) detection. Patient
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#5 had a history of AML with a normal diploid karyotype and del(7p) was detected at AML relapse after 30 months in remission. The patient responded initially to therapies with clearance of del(7p), but relapsed soon after with reappearance of del(7p). Patient died after 18 months since del(7p) detection Patient #6 had a history of splenic marginal zone lymphoma which was treated with FCR, he developed t-MDS 76 months later with an abnormal karyotype of 47,XX,+8[5]/46,XX[15]. Thirteen months later, the patient experienced AML (with myelodysplasiarelated changes) progression, at this time +8 was no longer detected and del(7p) emerged. Patient died of AML at 0.3 month after del(7p) detection. Patient #7 had a history of AML with t(8;21) who was successfully treated and achieved clinical, morphological and cytogenetic remission for 7 years. He then developed t-MDS (MDS with excess blasts) with del(7p), and 21 months later, progressed to AML (with myelodysplasiarelated changes) with clonal evolution and the karyotype showed 46,XX,del(7)(p15p22)[3]/49,XX,del(7)(p15p22),+8,+12,+21[17]. She died of AML 4 months later. Patient #8 had a history of breast cancer treated with chemotherapy and radiotherapy. The baseline karyotype was unknown. She developed t-MDS (MDS with multilineage dysplasia) 108 months later with detection of del(7p), and progressed to CMML-2 after 5 months. Patient died of disease 1 month later. Overall, the presence of a large del(7p) clone correlated well with disease status in these 7 patients. Three patients had del(7p) as a small clone. Patient #3 had del(7p) detected at the time of initial diagnosis of AML that was refractory to therapies, del(7p) was detected in the first 2 BM samples in 2/20 metaphases; however, the next 2 BM samples yielded insufficient metaphases (5 and 1, respectively) without del(7p) detection. Patient #9 and #10 had a similar clinical course, both had a history of AML and del(7p) was detected when both patients were in clinical and morphological remission. Del(7p) was persistently detected as a small clone in BM samples for 12–27 months and then disappeared. These 2 patients had unremarkable BM morphologic findings and had a normal complete blood count in all follow-up BM/PB samples. Both patients were alive and remained in remission at last clinical follow-up. 3.3. Molecular findings Patients were tested for a variety of gene mutations determined by disease type and protocols active at the time. The genes tested (Table 2) included NRAS (n = 6), KRAS (n = 6), NPM1 (n = 5), FLT3 (n = 5), CEBPA (n = 3), KIT (n = 2), and JAK2 (n = 2). Case #3 had NRAS mutation detected at the initial diagnosis of AML, the same time when a small clone of del(7p) was detected; case #4 and #5 had FLT3-ITD and NPM1 mutation detected at the initial diagnosis of AML, and these two mutations were detected again at AML relapse when del(7p) was detected; gene mutations were not detected in other cases. 4. Discussion Del(7p) as a sole abnormality is very rare, mainly detected in patients with myeloid neoplasms, including AML, MDS, CMML to PMF in this cohort, and presenting either as de novo, therapyrelated or relapsed disease. In this study, we present evidence that a large clone (>50% of metaphases) of del(7q) appears to be a high risk cytogenetic abnormality associated with progression or relapse of disease. However, del(7p) can also be seen as “clonal cytogenetic abnormality of uncertain significance” if they are only detected in a low number of metaphases. There were 4 patients with AML with isolated del(7p) in this study. One patient (#3) had del(7p) at the time of diagnosis. In
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H.D. Gur et al. / Leukemia Research 55 (2017) 18–22
Table 1 Demographic and clinical information. Case#
Age/Sex
Prior diagnosis
Prior therapy
Interval (Mon)
BM Diagnosis
Therapies after del(7p)
Follow-up
OS (mon)/Outcome
1
63/M
No
No
0
CMML
To AML
21/DOD
2
53/M
No
No
0
PMF
To AML
95* /ACR
3
66/F
No
No
0
AML-M5a
Refractory AML
2/DOD
4
60/F
AML-M2
Chemotherapy (induction 3 + 7)
7
Relapsed AML
Refractory AML
8/DOD
5
60/F
AML-M2
Relapsed AML
Refractory AML
18/DOD
6 7
47/F 49/F
Splenic MZL AML with t(8;21)
Chemotherapy 30 (induction 3 + 7) FCRx8 76 cyclophosphamide,88 ara-C, topotecan
Refractory AML To AML
0.3/DOD 25/DOD
8
68/F
Breast cancer
108
t-MDS
To CMML-2
6* /DOD
9
41/M
AML-M2
15
Negative BM
Observation
In remission
35/ACR
10
50/M
AML-M2
Adriamycin, Taxol Radiotherapy Chemotherapy (induction 3 + 7), SCT Chemotherapy (induction 3 + 7)
Idarubicin, cytarabine Fludarabine + busulfan Plerixafor + clofarabine,Ruxolitinib Plerixafor + Cytarabine + Daunorubicin, Vidaza Voreloxin + Cytarabine, Plerixafor Decitabine Decidabin, Filanesib, Mylotarg, Vidaza Decitabine
12
Negative BM
Observation
In remission
107/ACR
AML-MRC t-MDS
Interval: from the initiation of cytotoxic therapy to the detection of del(7p). OS: overall survival, from the date of del(7p) detection to the date of death or last follow-up for alive patients. ACR: alive with complete remission; AML: acute myeloid leukemia; AML-M2: acute myeloid leukemia with maturation; AML-M5a: acute monoblastic leukemia; AML-MRC: acute myeloid leukemia with myelodysplasia-related changes; BM: bone marrow; CMML: chronic myelomonocytic leukemia; DOD: died of disease; F: female; FCR x 8: Fludarabine, cyclophosphamide, rituximab for 8 cycles; M: male; MDS: myelodysplastic syndromes; MZL: marginal zone lymphoma; PMF: Primary myelofibrosis; SCT: stem cell transplant; t-: therapy-related. * Received allogeneic stem cell transplant. Table 2 Cytogenetic and molecular information. Case# Prior karyotype
Del(7p) clone*
CG FU Del(7p) outcome
1 2 3 4 5 6 7 8 9 10
46,XY,del(7)(p13p15)[18] 46,XY,del(7)(p15)[20] 46,XX,del(7)(p12)[2] 46,XX,del(7)(p15p21) [20] 46,XX,del(7)(p15p21)[16] 46,XX,del(7)(p12)[20] 46,XX,del(7)(p15p22)[20] 46,XX,del(7)(p15p22)[20] 46,XY,del(7)(p15)[5] 46,XY,del(7)(p15p22)[6]
8x 9x 3x 5x 4x none 4x 5x 8x 5x
No No No 46,XX[20] 46,XX[20] 47,XX,+8 [5]/46,XX[15] 45,X,-X,t(8;21) (q22;q22)[16] Unknown Unknown 46,XY[20]
Persistent Persistent** persistent Persistent, + new clone Persistent NA Clonal evolution Persistent Disappeared after 12 m Disappeared after 27 m
Gene mutation tested Mutated
Unmutated
None None NRAS FLT3-ITD, NPM1 FLT3-ITD, NPM1 N/A None None None None
NRAS, KRAS, FLT3 JAK2 KRAS, NPM1, CEBPA, IDH1/2, KIT KRAS, NRAS, IDH1/2, CEBPA, JAK2 KRAS, NRAS, KIT N/A FLT3, NPM1 FLT3, NPM1, KRAS, NRAS, IDH1/2, DNMT3A, CEBPA FLT3 KRAS, NRAS, FLT3
CG: cytogenetics; FU: follow-up; NA: not applicable. * A total of 20 metaphases were analyzed, only the clone with del(7p) was listed here, the remaining metaphases showed a normal diploid karyotype. ** Disappeared after stem cell transplant.
this patient, del(7p) was detected in 2/20 metaphases and then became undetectable during the course of disease, suggesting that del(7p) might not be directly associated with AML pathogenesis. In contrast, the other 3 AML patients were found to have isolated del(7p) either at disease relapse or when MDS progressed to AML. The acquisition of del(7p) in these 3 patients was associated with refractoriness to therapy and short survival (range, 0.3–18 months). These findings suggest that in AML, isolated del(7p) likely presents as an acquired clonal cytogenetic abnormality, closely related to disease progression or relapse, and may be associated with a poor outcome. In contrast to AML, in 4 patients who presented with t-MDS, CMML or PMF, sole del(7p) was detected at the time of
diagnosis. All 4 patients had a large and persistent del(7p) clone, and all patients showed disease progression and/or transformed to AML within 2 years. Except for 1 patient (case #2) who received HSCT, the other 3 patients died shortly after disease progression. Although the number of patients was small and there were other confounding factors, a major clone of del(7p) appeared to be a cytogenetic abnormality associated with a high risk of progression and a poor patient outcome. We reported previously that in the post chemotherapy setting, some clonal cytogenetic abnormalities, including del(7q), can be clinically “silent” or appear to be without clinical significance [9,10]. These types of cytogenetic abnormalities often present in isolation,
H.D. Gur et al. / Leukemia Research 55 (2017) 18–22
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Fig. 1. Chromosome analysis showed del(7p) at different breakpoints. (A) karyotype of case #2: 46,XY,del(7)(p15); (B) case #1: del(7)(p13p15); (C) case #4: del(7)(p15p21); (D) case #6: del(7)(p12); (E) case #7: del(7)(p15p22).
involve a small number of metaphases, and may or may not be persistent in follow-up BMs. Similarly, small clone of del(7p), if it emerges in patients who have received prior cytotoxic therapies, presented as a sole abnormality and involves a small number of metaphases, does not seem to be disease-associated. This was evident in 2 patients (cases #9-10) who received chemotherapies for AML and achieved complete remission, but 12–15 months later, the patients were found to have a small del(7p) clone in their BMs. In both patients, del(7p) was repeatedly detected in BM for 12–27 months, but eventually became undetectable. Both patients remained in remission and showed no evidence of secondary myeloid neoplasms during the follow-up period (up to 107 months). These observations indicate that not all del(7p) are disease-associated, especially while it presents as a small clone. It is worth to mention that the clone size could be more precisely estimated by interphase fluorescence in situ hybridization (FISH), especially in patients #3, 9 and 10 with low numbers of metaphases. However, due to no archived materials, FISH was not performed in this study. Based on our previous studies [10–12], the clone size determined by metaphases is often larger but proportionally correlated with the clone size detected by interphase FISH. Studies have confirmed that MDS/AML patients with complete loss of chromosome 7 (-7) have a much poorer outcome compared with patients who have del(7q). These results suggest that
there are critical genetic materials located on chromosome 7p that might contribute to the poor outcomes of patients with MDS/AML. Although no gene has been identified on 7p that appears to be associated with myeloid neoplasms and poor outcome, there are several putative genes on 7p that may be associated with hematopoietic malignancies. One of the genes is in the IKAROS family zinc finger 1 (IK2F1) located on 7p12. IK2F1 is a transcription factors involved in chromatin remodeling and plays a key role in hematopoietic stem cell maintenance, and B- and T- cell lymphopoiesis. IKZF1 and ETV6 are components of a network of heptad transcription factors that regulate genes in hematopoietic stem and progenitor cells, dysregulation of these genes in AML is associated with poor prognosis [13]; Others also have shown that deletion of IKZF1 is associated with unfavorable prognosis in childhood BCP-ALL [14] and a higher relapse risk and worse survival in adults with common BCP-ALL [15]. Recent studies also suggested that IKZF1 was involved in myeloid differentiation and might have a role in oncogenesis of pediatric AML with loss of chromosome 7 [16]. Another putative gene, ubiquitin-specific protease gene (UPS 42), located on 7p22, might play a pathogenetic role in MDS and AML through chromosome rearrangement [17,18]. Nonetheless, the genetic mechanisms underlying this abnormality are largely unknown and require further investigation. Unfortunately, no remaining BM sample was available to enable us to do further studies (such as array compar-
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ative genomic hybridization, aCGH), to narrow down the critical regions in 7p. In conclusion, del(7p) as a sole abnormality can be rarely detected in bone marrows of patients with a variety of myeloid neoplasms. When present as a large clone, isolated del(7p) appears to be associated with a high risk for disease progression, refractoriness to therapy and an inferior outcome. On the other hand, when del(7p) only involves a small number of metaphases, it can be a transient finding that poses no clinical consequence. We suggest these findings also emphasize a more general principle that the size of cytogenetic clone, as well as a specific chromosomal abnormality, is important information to consider in the risk assessment of patients with myeloid neoplasms. Acknowledgements The authors would like to thank colleagues from department of hematopathology and clinical cytogenetic laboratory for their great inputs. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.leukres.2017. 01.016. References [1] P.L. Greenberg, H. Tuechler, J. Schanz, G. Sanz, G. Garcia-Manero, F. Sole, et al., Revised international prognostic scoring system for myelodysplastic syndromes, Blood 120 (12) (2012) 2454–2465. [2] J. Schanz, H. Tuchler, F. Sole, M. Mallo, E. Luno, J. Cervera, et al., New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge, J. Clin. Oncol. 30 (8) (2012) 820–829. [3] O. Pozdnyakova, P.M. Miron, G. Tang, O. Walter, A. Raza, B. Woda, et al., Cytogenetic abnormalities in a series of 1,029 patients with primary myelodysplastic syndromes: a report from the US with a focus on some undefined single chromosomal abnormalities, Cancer 113 (12) (2008) 3331–3340. [4] S.H. Swerdlow, C. Campo, N.L. Harris, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Edited by International Agency for Research on Cancer, The International Agency for Research on Cancer, Lyon, 2008.
[5] I. Cordoba, J.R. Gonzalez-Porras, B. Nomdedeu, E. Luno, R. de Paz, E. Such, et al., Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome, Cancer 118 (1) (2012) 127–133. [6] H. Dohner, E.H. Estey, S. Amadori, F.R. Appelbaum, T. Buchner, A.K. Burnett, et al., Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet, Blood 115 (3) (2010) 453–474. [7] N.A. Heerema, J.B. Nachman, H.N. Sather, M.K. La, R. Hutchinson, B.J. Lange, et al., Deletion of 7p or monosomy 7 in pediatric acute lymphoblastic leukemia is an adverse prognostic factor: a report from the Children’s Cancer Group, Leukemia 18 (5) (2004) 939–947. [8] L.G. Shaffer, J. McGowan-Jordan, M. Schmid, An International System for Human Cytogenetic Nomenclature, S. Karger Basel, 2016. [9] G. Tang, S.A. Wang, V. Lu, H.C. Lee, M.H. Qazilbash, X.I. Wang, et al., Clinically silent clonal cytogenetic abnormalities arising in patients treated for lymphoid neoplasms, Leuk. Res. 38 (8) (2014) 896–900. [10] R.S. Goswami, S.A. Wang, C. DiNardo, Z. Tang, Y. Li, W. Zuo, et al., Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms, Mod. Pathol. 29 (7) (2016) 727–734. [11] C.C. Yin, J. Peng, Y. Li, R.K. Shamanna, T. Muzzafar, C. DiNardo, et al., Clinical significance of newly emerged isolated del(20q) in patients following cytotoxic therapies, Mod. Pathol. 29 (8) (2016) 939. [12] G. Tang, R.S. Goswami, C.S. Liang, C.E. Bueso-Ramos, S. Hu, C. DiNardo, et al., Isolated del(5q) in patients following therapies for various malignancies may not all Be clinically significant, Am. J. Clin. Pathol. 144 (1) (2015) 78–86. [13] A. Unnikrishnan, Y.F. Guan, Y. Huang, D. Beck, J.A. Thoms, S. Peirs, et al., A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network, Nucl. Acids Res. (2016), Epub ahead of print. [14] J.M. Boer, A. van der Veer, D. Rizopoulos, M. Fiocco, E. Sonneveld, H.A. de Groot-Kruseman, et al., Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study, Leukemia 30 (1) (2016) 32–38. [15] Q.M. Yao, K.Y. Liu, R.P. Gale, B. Jiang, Y.R. Liu, Q. Jiang, et al., Prognostic impact of IKZF1 deletion in adults with common B-cell acute lymphoblastic leukemia, BMC Cancer 16 (2016) 269. [16] J.D. de Rooij, E. Beuling, M.M. van den Heuvel-Eibrink, A. Obulkasim, A. Baruchel, J. Trka, et al., Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia, Haematologica 100 (9) (2015) 1151–1159. [17] K. Paulsson, A.N. Bekassy, T. Olofsson, F. Mitelman, B. Johansson, I. Panagopoulos, A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42, Leukemia 20 (2) (2006) 224–229. [18] N. Foster, K. Paulsson, M. Sales, J. Cunningham, M. Groves, N. O’Connor, et al., Molecular characterisation of a recurrent, semi-cryptic RUNX1 translocation t(7;21) in myelodysplastic syndrome and acute myeloid leukaemia, Br. J. Haematol. 148 (6) (2010) 938–943.