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Journal of Leukemia
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Myeloid Neoplasms Associated with t(3;12)(q26.2;P13) Are Clinically Aggressive and Frequently Harbor FLT3 Mutations: A Report of 8 Cases and Review of Literature

Xiaohong I Wang1, Xinyan Lu1, C. Cameron Yin 1, Lian Zhao1, Carlos E Bueso-Ramos1, Jeffrey Medeiros L1, Shaoying Li2, Heesun J Rogers3, Eric D Hsi3 and Pei Lin1*
1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA
2Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37235, USA
3Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA
Corresponding Author : Pei Lin
Department of Hematopathology
The University of Texas MD Anderson Cancer Center
1515 Holcombe Boulevard
Unit 305 Houston, Texas 77030-4009, USA
Tel: 713-794-1746
E-mail: peilin@mdanderson.org
Received July 18, 2014; Accepted September 20, 2014; Published September 25, 2014
Citation: Wang XI, Lu X, C. Cameron Yin, Zhao L, Bueso-Ramos CE, et al. (2014) Myeloid Neoplasms Associated with t(3;12)(q26.2;P13) Are Clinically Aggressive and Frequently Harbor FLT3 Mutations: A Report of 8 Cases and Review of Literature. J Leuk (Los Angel) 2:161. doi: 10.4172/2329-6917.1000161
 
Copyright: © 2014 Wang X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 
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Abstract

The t(3;12)(q26.2;p13) involving EVI1/ETV 6 is a rare recurrent translocation that has been identified in myeloid neoplasms. The clinicopathologic features of these are not well characterized. We identified 5 cases of Acute Myeloid Leukemia (AML) and 3 cases of Myelodysplastic Syndrome (MDS) associated with t(3;12)(q26.2;p13). There were 5 men and 3 women, with a median age of 60 years. The AML cases included 2 de novo, 2 arising from prior MDS and 1 relapsed AML. The median bone marrow blast count was 50% (range, 35-91%). Dysplasia involving one or more lineages dysplasia was noted in all cases. Of the 3 MDS cases, two were classified as refractory anemia with excess blasts and one therapy related. Two that had follow up data rapidly evolved to AML within 6 months. Conventional cytogenetic analysis showed t(3;12) (q26.2;p13) in all neoplasms and additional abnormalities in 5 patients, Including chromosome 7 abnormalities in 3 patients. FISH confirmed ETV6 rearrangement in all 3 cases assessed and EVI1 rearrangement in both cases assessed. FLT3 ITD was identified in 3 of 5 cases assessed. The median overall survival was 12 months (range, 7-58 months). We conclude that t(3;12) can occur as either a primary or secondary event in myeloid neoplasms. The t(3;12) is associated with multilineage dysplasia, chromosome 7 aberrations and an aggressive clinical course.

Keywords
Myeloid neoplasms; t(3;12)(q26.2;p13); EVI1; ETV6; FLT3; Chromosome 7
Introduction
Disruption of chromosome locus 3q26 is an uncommon recurrent cytogenetic abnormality that occurs in a small percentage of cases of acute myeloid leukemia (AML) or Myelodysplastic Syndrome (MDS). The ecotropic viral integration site 1 (EVI1) gene, located on chromosome 3q26.2, has been shown to be activated in at least a subset of these meyleoid neoplasms. EVI1 is activated in various AML associated cytogenetic abnormalities, such as inv(3)(q21q26.2)/EVI1- GATA1 or t(3;3)(q21;q26.2)/EVI1-GATA1.
The t(3;12)(q26.2;p13) is a rare recurrent event in cases of AML, MDS, and blast phase of CML [1-3]. The ETV6 gene (ETS variant gene 6), also called Translocation Ets Leukemia (TEL), is located on 12p13 and encodes for a transcription factor that is a target of deletions and translocations in both myeloid and lymphoid malignancies. Various partner genes in reciprocal translocations involving 12p13 have been described. ETV6 rearrangements are much less frequent in myeloid neoplasms [4].
The clinical and molecular features of myeloid neoplasms associated with t(3;12)(q26.2; p13) are not as well understood as those associated with inv(3)/t(3;3). In this study, we comprehensively described features of 8 patient with myeloid neoplasms associated with t(3;12)(q26.2; p13).
Materials and Methods
 
We searched the database of the Clinical Cytogenetics Laboratory for cases of myeloid neoplasms associated with t(3;12)(q26.2;p13) detected by conventional cytogenetic analysis. Two cases were also obtained from the Department of Pathology, Vanderbilt University School of Medicine and Cleveland Clinic, respectively. The diagnosis was based on the 2008 WHO criteria. Wright-Giemsa-stained BM aspirate smears and touch imprints and H&E-stained Bone Marrow core biopsy and clot sections were reviewed. This study was conducted according to an institutional review board-approved protocol.
Multicolor flow cytometry immunophenotypic analysis was performed on BM aspirate specimens using a FACScan instrument (Becton-Dickinson, San Jose, Calif) as described previously [5]. The blast population was gated using right-angle side scatter and CD45 expression. The panel of monoclonal antibodies included reagents specific for CD3, CD5, CD7, CD13, CD14, CD19, CD33, CD34, CD38, CD64, CD117, HLA-DR, TdT, and myeloperoxidase (Becton- Dickinson).
Bone marrow aspirate specimens were analyzed by conventional cytogenetic analysis as described previously [6]. Metaphases were banded by the standard GTG method. Karyotypes were reported according to the 2013 International System for Human Cytogenetic Nomenclature [7].
Fluorescence in Situ Hybridization (FISH) was performed using a Vysis LSI ETV6 dual color, breakapart gene rearrangement probe which hybridizes to band 12p13. The EVI1 dual-color, breakapart probe was also used to detect EVI1 gene rearrangement at 3q26. For each specimen, 200 interphases were analyzed. The FISH images were captured and analyzed by Applied Imaging software (Santa Clare, CA).
Analyses for FLT3 Internal Tandem Duplication (ITD) and codon 835/836 point mutation were performed by polymerase chain reaction (PCR)-based amplification of genomic DNA and capillary electrophoresis as described previously [8]. Codons 12, 13, and 61 of KRAS and NRAS were sequenced following PCR amplification using Sanger sequencing or a pyrosequencing-based method as previously described [9]. NPM1 mutations spanning codons 956 to 971 of exon 12 were detected by PCR followed by capillary electrophoresis as described previously [10]. KIT (exons 8 and 17) mutation was detected by direct Sanger sequencing on an ABI Prism 3100 Genetic Analyzer [10,11].
The overall survival (OS) was calculated from date of diagnosis of either MDS or AML associated with t(3;12)(q26.2; p13) until death from any cause (censored at last follow-up) or date of last follow-up.
Results
Clinical findings
The clinical and morphological features are summarized in Table 1. Of the 8 patients with t(3;12)(q26.2;p13), there were 5 men and 3 women, with a median age of 60 years (range, 33-79 years). Presenting symptoms include fever, chills, general malaise, weakness and night sweats (cases 1, 2), fatigue (cases 3,5,6,8), gum bleeding (case 4) and upper airway infection (case 7). Physical exam found lymphadenopathy (cases 1,4) and a palpable spleen (case 1). None had extra medullary involvement at the diagnosis. Five cases were classified as AML and 3 cases MDS. All patients had anemia with a median hemoglobin level of 8.9 g/dL (range, 6.8 to 12.3 g/dL [68-123 g/L]; reference range, 14-18 g/dL [140-180 g/L] for men and 12-14 g/dL [120-140 g/L] for women) and thrombocytopenia with a median platelet count of 52 × 109/L (range, 24-111 × 109/L; reference range, 140-440 × 109/L). The median white blood cell (WBC) count was 62.6 k/uL (rang, 1.9-129.5 k/uL) for the 5 cases of AML with a median peripheral blood blast count of 31% (range, 21-88%). The patients with MDS had a median WBC of 4.0 k/ uL (range, 1.8-7.6 k/uL) with a median peripheral blood blast count of 1% (range, 0% to 3%).
Serum chemistry results were generally unremarkable except the lactate dehydrogenase level was elevated in 2 of 6 patients assessed (range, 173-4,183 U/L; median, 489 U/L; reference range, 313-618 IU/L), and the β2-microglobulin level were elevated in 1 patient, 7.3 × 10–3 g/L ( reference range, 0.6-2.0 × 10–3 g/L) (data not shown).
Morphologic findings
Peripheral blood smears showed circulating blasts in 7/8 cases (range, 1%-88%), anemia with mild to moderate anisopoikilocytosis (5/6 cases), nucleated red blood cells (2/5 cases), absolute monocytosis (3/5 cases).
Bone marrow aspirate smears showed multilineage dysplasia in all 8 cases. Five of 8 (63%) cases showed megakaryocytic hypoplasia. Small hypolobated megakaryocytes were observed in 7/7 cases evaluable (Figure 1). Blasts ranged from 1% to 18% in cases of MDS and 35 % to 91% in case of AML.
The 8 cases were classified as follows. Two de novo AML: one was AML without maturation (case 1) and the other acute monoblastic leukemia (case 2). Two were AML that evolved from MDS diagnosed 7 and 11 months earlier and were classified as AML with myelodysplasiarelated changes (case 3 and 4). One case of AML was diagnosed at time of relapse (case 5). Two cases of MDS were classified as refractory anemia with excess blasts (RAEB-1 and RAEB-2) (cases 6 and 7) and 1 patient had therapy-related MDS following therapy for 8 months (case 8).
Immunophenotypic findings
Flow cytometric immunophenotypic analysis of BM aspirate specimens from the 5 AML cases showed that the blasts were of myeloid origin. Blasts were positive for CD13, CD33, CD34, CD117, and HLADR in all cases. They were also positive for CD5 (partial, 1/3, 33%), CD7 (partial, 2/4, 50%), CD14 (1/2, 50%), CD15 (3/3, 100%), CD38 (2/3, 67%), and CD64 (2/3, 67%).
 
Cytogenetic findings
 
All 8 cases carried the t(3;12)(q26.2;p13). Three (37%) cases (cases 5-7) had t(3;12)(q26.2;p13) as the sole abnormality at the time of first detection (Table 2). The other 5 cases (63%) showed additional chromosomal abnormalities, including monosomy 7 (case 1), del(11) (q23.1) (case 2), and add(7)(q11.2) (case 3), del10(q22q24) (case 4), r(7) and monosomy 7 (case 8). In case 5, t(3;12) was not identified in the leukemic blasts at initial diagnosis of AML, but was detected 9 months later at time of relapse. In the whole cohort (n=8), the median number of additional chromosomal abnormalities was 1 (range, 0-2). All 4 patients with available initial karyotypes had other cytogenetic abnormalities prior to detection of t(3;12): add 7 (case 3), monosomy 7 (case 8), t(10;12)(q24;p13) (case 4) and 46,X, t(X;19)(p11.2;p13.1) (case 5) preceded that of t(3;12) by approximately 11, 12, 6 and 10 months, respectively, suggesting that t(3;12) evolved as a secondary event. In cases 1, 2 and 6, the initial karyotype was unknown. There was no cytogenetic follow up for case 7.
 
Fluorescence in situ hybridization was performed in a subset of cases. ETV6 rearrangements were observed in all 3 cases assessed and EVI1 rearrangements were detected in both cases assessed (Figure 2).
 
Molecular findings
 
FLT3-ITD was identified in 3 of 5 cases assessed (cases 1, 2 and 4). KRAS mutation was detected in 2 of 5 cases (G12D in case 4 and G12A in case 8). NRAS mutation (1/3, G13D in case 4) and KIT D816V mutation (1/3, D816V in case 3) were also identified (Table 1D).
 
Clinical Outcome
 
Clinical follow-up was available for 7 patients. All patients received multi-agent chemotherapy. Three also underwent stem cell transplantation (cases 1, 2 and 8). At last follow-up, 5 patients had died and 2 were alive. Overall Survival (OS) ranged from 7 to 58 months with a median of 11 months. For the 3 patients who underwent transplantation, the median survival was 17 months (range, 12-58 months). The median survival for the 4 patients who did not undergo transplantation was 7 months (range, 7-11 months). There was no significant difference in OS between patients who did or did not undergo transplantation. Of the two cases of MDS that had follow up data (cases 6 and 8), the disease evolved to AML within 2 and 6 months, respectively, after detection of t(3;12), with the bone marrow blast count rising from 8% to 71%, and from 2 to 25% respectively (Table 1E).
 
Discussion
The t(3;12)(q26.2;p13) was first reported by Secker-Walker et al in 3 patients as part of a larger series of 66 myeloid neoplasms with chromosomal abnormalities in the 3q26.2 region [12]. To date, 42 patients have been recorded in the Mitelman database, including AML (n=35), CML (n=4), and MDS (n=3) [13]. However, data regarding these cases are limited (Table 3) [1,14]. Our study is the largest series to date and provided both conventional cytogenetic as well as molecular genetic findings that were missing in many of the previous case reports.
In this study, we show that myeloid neoplasms associated with t(3;12) are mostly adults who usually presented with anemia and had poor clinical outcome. Multilineage dysplasia was consistently observed in all patients with frequent small hypolobated megakaryocytes. Karyotypic abnormalities in addition to t(3;12) were common, with monosomy 7 occurring in approximately half of the cases. Furthermore, the t(3;12) was preceded by other karyotypic aberrations in 4 patients whose initial cytogenetic data were available, indicating that the t(3;12) was likely a secondary event or existed as a small subclone initially in these patients. The frequent association with chromosome 7 abnormalities is in accordance with the others reported in Mitelman database (Table 2): 21 of 38 (55%) AML and MDS cases [12,13] carried the t(3;12)(q26.2;p13) as a sole abnormality. Nine (24%) cases had additional chromosome 7 abnormalities, with loss of part or all of chromosome 7 (8/9, 89%) being the most common. We also showed FLT3-ITD mutations in over half of the cases assessed, a frequency that appears to be higher than the reported overall frequency of 20% to 30% in AML patients [14] and a reported frequency of 18% in balanced t(3q26;v) AML [1].
The EVI1 proto-oncogene is located on human chromosome 3q26. Its transcriptional activation is relatively common in myeloid malignancies and has been reported in up to 10% of AML, CML in blast phase, and MDS. [15]. The EVI1 protein is a transcriptional regulator with DNA-binding zinc finger domains. Overexpression of EVI1 is an indicator of poor prognosis in myeloid malignancies. The major cellular effects are promoting proliferation, interfering with myeloid differentiation and preventing cellular apoptosis. In retrovirallytransduced marrow cell recipient mice, coexpression of EVI1 and Trib1 accelerates leukemogenesis [16]. EVI1 binds CCAAT/enhancer binding protein-ε (C/EBP-ε) and deregulates terminal differentiation of granulocytes [17]. Kurokawa et al. demonstrated that EVI1 inhibits c-Jun N-terminal kinase (JNK) to suppress stress induced apoptosis [18].
A number of inversions and translocations have been described in human AML and Myelodysplastic Syndrome (MDS) marrow cells involving chromosome 3q26, where the human gene is located. The most common EVI1 chromosomal rearrangements include inv(3), t(3;3), t(3;12) and t(3;21). The t(3;12)(q26;p13) results in a fusion protein involving ETV6 (also termed TEL), an ETS family transcription factor required for normal hematopoiesis. The prototype of AML/MDS with EVI1 disruption is inv(3)/t(3;3)/EVI1-GATA1, which is recognized as a distinct entity in the current World Health Organization (WHO) classification. These patients often present de novo or arise from a prior MDS, with frequent concurrent chromosomal 7 aberrations and have a short overall survival [1,19]. Bone Marrow (BM) typically shows increased small hypolobated megakaryocytes and multilineage dysplasia. It is unclear if cases in which 3q26.2/EVI1 partners with genes other than GATA1 behave similarly to those with inv(3)/t(3;3) in clinical presentation and outcome. The t(3;12) is thought to juxtapose ETV6 upstream of EVI1 gene resulting in EVI1 overexpression. We have demonstrated here that these cases are similar to those of AML/ MDS with inv(3)/t(3;3) in many of the features described above and justify their classification in the same subgroup as AML with inv(3)/t(3;3). As inv(3)/t(3;3) is identified following -7 in some cases, we also observed that t(3;12) may emerge several months after other cytogenetic aberrations or during relapsed AML. Interestingly, the emergence of t(3;12) was accompanied by rapid evolution to AML, within 6 months, in the MDS cases. These observations suggest that the t(3;12) may signify a general genetic instability and is a secondary event in many cases that contributes to disease progression. Based on rapid progression to AML, we also believed that the cases with a blast count in the range of MDS be still considered as AML in a similar approach as that of AML with t(8;21) or inv(16).
In summary, we have described 8 cases of AML or MDS with t(3;12)(q26.2;p13). Similar to cases with inv(3)q21q26.2) or t(3;3)(q21;q26.2), they usually show dysplasia, associated with abnormalities of chromosome 7, aberrant expression of CD7 in blasts and with short survival despite multiple chemotherapy and bone marrow transplantation. However, unlike cases with inv(3) q21q26.2) or t(3;3)(q21;q26.2), these cases are frequently associated with thrombocytopenia, megakaryocytic hypoplasia and FLT3-ITD mutation. The t(3;12) also occurred following other cytogenetic aberrations, suggesting it existed as a small subclone initially or emerged a secondary event in some cases. Overall, the findings suggest that this group of patients should be classified in the same subgroup as AML with inv3/t(3;3).
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