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KMT2A-CBL fusion in rapidly progressive myeloid disorder

      Acute myeloid leukemia (AML) deriving from myelodysplastic syndrome (MDS) accounts for 24-35% of all AML cases [
      • Arber DA
      • Orazi A
      • Hasserjian R
      • et al.
      The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
      ], and MDS with abnormal karyotype is strongly associated with progression to AML [
      • Germing U
      • Strupp C
      • Kuendgen A
      • et al.
      Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes.
      ]. Alterations of lysine methyltransferase 2A (KMT2A, previously MLL) gene on 11q23.3 are implicated in various hematopoietic malignancies, including de novo AML [
      • Bill M
      • Mrozek K
      • Kohlschmidt J
      • et al.
      Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A.
      ], MDS [
      • Bain BJ
      • Moorman AV
      • Johansson B
      • Mehta AB
      • Secker-Walker LM.
      Myelodysplastic syndromes associated with 11q23 abnormalities. European 11q23 Workshop participants.
      ] and therapy-related leukemias involving anti-topoisomerase II, alkylating agents and radiotherapy [
      • Secker-Walker LM
      • Moorman AV
      • Bain BJ
      • Mehta AB.
      Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop.
      ,
      • Super HJ
      • McCabe NR
      • Thirman MJ
      • et al.
      Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II.
      ]. KMT2A has a few recurrent fusion partners; however, 10% of KMT2A-driving fusions involve over 100 different partner genes [
      • Meyer C
      • Burmeister T
      • Groger D
      • et al.
      The MLL recombinome of acute leukemias in 2017.
      ]. Therefore, the main strategy for detection involves florescent in situ hybridization (FISH) using a break apart probe set for KMT2A followed by karyotype to potentially elucidate the partner. Two reported partners, CBL and ARHGEF12, are distal to KMT2A on 11q23.3 and an interstitial cryptic deletion forms the driving fusions. Here, we report a 74-year-old male who initially presented with del(13q) and U2AF1-altered MDS, which rapidly progressed to AML with a 3′ KMT2A deletion resulting in a KMT2A-CBL fusion and tetrasomy 8. This report adds to the sparse literature involving a deletion forming KMT2A fusion, emphasizing the importance of integrative genetic testing, and highlights the unique gain and subsequent loss of the fusion in-line with disease evolution.

      Keywords

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      References

        • Arber DA
        • Orazi A
        • Hasserjian R
        • et al.
        The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
        Blood. 2016; 127 ([published Online First: Epub Date]): 2391-2405https://doi.org/10.1182/blood-2016-03-643544
        • Germing U
        • Strupp C
        • Kuendgen A
        • et al.
        Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes.
        Haematologica. 2006; 91: 1596-1604
        • Bill M
        • Mrozek K
        • Kohlschmidt J
        • et al.
        Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A.
        Proc Natl Acad Sci U S A. 2020; 117 ([published Online First: Epub Date]): 26340-26346https://doi.org/10.1073/pnas.2014732117
        • Bain BJ
        • Moorman AV
        • Johansson B
        • Mehta AB
        • Secker-Walker LM.
        Myelodysplastic syndromes associated with 11q23 abnormalities. European 11q23 Workshop participants.
        Leukemia. 1998; 12 ([published Online First: Epub Date]): 834-839https://doi.org/10.1038/sj.leu.2401020
        • Secker-Walker LM
        • Moorman AV
        • Bain BJ
        • Mehta AB.
        Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop.
        Leukemia. 1998; 12 ([published Online First: Epub Date]): 840-844https://doi.org/10.1038/sj.leu.2401021
        • Super HJ
        • McCabe NR
        • Thirman MJ
        • et al.
        Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II.
        Blood. 1993; 82: 3705-3711
        • Meyer C
        • Burmeister T
        • Groger D
        • et al.
        The MLL recombinome of acute leukemias in 2017.
        Leukemia. 2018; 32 ([published Online First: Epub Date]): 273-284https://doi.org/10.1038/leu.2017.213
        • Barber KE
        • Ford AM
        • Harris RL
        • Harrison CJ
        • Moorman AV.
        MLL translocations with concurrent 3′ deletions: interpretation of FISH results.
        Genes Chromosomes Cancer. 2004; 41 ([published Online First: Epub Date]): 266-271https://doi.org/10.1002/gcc.20082
        • Haferlach C
        • Grossmann V
        • Kohlmann A
        • et al.
        Deletion of the tumor-suppressor gene NF1 occurs in 5% of myeloid malignancies and is accompanied by a mutation in the remaining allele in half of the cases.
        Leukemia. 2012; 26 ([published Online First: Epub Date]): 834-839https://doi.org/10.1038/leu.2011.296
        • Krivtsov AV
        • Hoshii T
        • Armstrong SA.
        Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia.
        Cold Spring Harb Perspect Med. 2017; 7 ([published Online First: Epub Date])https://doi.org/10.1101/cshperspect.a026658
        • Kales SC
        • Ryan PE
        • Nau MM
        • Lipkowitz S.
        CBL and human myeloid neoplasms: the CBL oncogene comes of age.
        Cancer Res. 2010; 70 ([published Online First: Epub Date]): 4789-4794https://doi.org/10.1158/0008-5472.CAN-10-0610
        • Chen B
        • Jiang L
        • Zhong ML
        • et al.
        Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia.
        Proc Natl Acad Sci U S A. 2018; 115 ([published Online First: Epub Date]): 373-378https://doi.org/10.1073/pnas.1717125115
        • Fu JF
        • Hsu JJ
        • Tang TC
        • Shih LY.
        Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia.
        Genes Chromosomes Cancer. 2003; 37 ([published Online First: Epub Date]): 214-219https://doi.org/10.1002/gcc.10204
        • Peterson JF
        • Baughn LB
        • Pearce KE
        • et al.
        KMT2A (MLL) rearrangements observed in pediatric/young adult T-lymphoblastic leukemia/lymphoma: A 10-year review from a single cytogenetic laboratory.
        Genes Chromosomes Cancer. 2018; 57 ([published Online First: Epub Date]): 541-546https://doi.org/10.1002/gcc.22666