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A novel recurrent AML1–ETO fusion: tight in vivo association with BCR–ABL1

Leukemia volume 27, pages 1397–1400 (2013)Cite this article

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In chronic myeloid leukemia (CML), the constitutively activated tyrosine kinase BCR–ABL1, the fusion protein resultant from t(9;22)(q34;q11), confers proliferation of myeloid progenitors. Additional chromosomal abnormalities, such as +8, i(17q) or t(3;21), are found in 7–10% of CML patients at diagnosis or may appear during disease progression.1 One of the most common rearrangements in acute myeloid leukemia (AML) is the t(8;21)(q22;q22) leading to the fusion of RUNX1 (alias, AML1) exon 5 to RUNX1T1 (alias, ETO) exon 2. Although it is conceivable that the proliferative benefit contributed by BCR–ABL1 and the impaired ability for differentiation conferred by RUNX1–RUNX1T1 could promote leukemia, these aberrations only rarely coexist in vivo.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 We report two patients with BCR–ABL1-positive CML and co-occurrence of RUNX1–RUNX1T1. Strikingly, in both cases a not previously described RUNX1–RUNX1T1 transcript was identified, which is due to the fusion of RUNX1 exon 6 (instead of exon 5) to RUNX1T1 exon 2.

Patient 1, a 54-year-old male, was diagnosed with CML in chronic phase in 2008. The white blood cell (WBC) count was 120 000/μl, and no peripheral blood (PB) blasts and no abnormal blast expansion in the bone marrow (BM) were observed. The karyotype, as assessed in 25 metaphases from BM, was 46,XY, t(9;22)(q34;q11). The BCR–ABL1 transcript was detected in BM with a ratio of 72.8% relative to ABL1. The patient was initiated on treatment with imatinib 400 mg daily and achieved complete hematologic response. After 14 months, he developed hematologic relapse, with WBC of 4800/μl, comprising 1% blasts, 2% promyelocytes and 22% eosinophils. In the BM, 15% blasts, which had a strong expression of CD117 (KIT), were detected, and the karyotype was 45,XY,t(8;21)(q22;q22),t(9;22)(q34;q11),−11[1]/93,XXYY,+8,+8,t(8;21)(q22;q22)x2, t(9;22)(q34;q11)x2,−11[8]. Twenty-four color fluorescence in-situ hybridization (FISH) on BM confirmed the presence of both translocations (data not shown); interphase FISH revealed BCR–ABL1 and RUNX1–RUNX1T1 rearrangements in ∼90% of the nuclei. BCR–ABL1 transcript was detected with a ratio of 37.1% and RUNX1–RUNX1T1 with 10.3% relative to ABL1 in the PB. No RUNX1–RUNX1T1 was detected in retrospective analyses of samples collected during chronic phase. The patient received dasatinib 70 mg daily and underwent allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-identical sibling 3 months later. He is currently in ongoing complete hematologic and molecular remission.

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Acknowledgements

Supported in part by the Fellowship Program of the Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany (to L Solari), the Research Committee of the University Freiburg, Germany (MER 785/10) (to H Becker) and the German Research Foundation (DFG Lu 429/7-1, CRC 992-C04) (to M Lübbert). We thank Milena Pantic (University of Freiburg Medical Center) for support in the cytogenetic analyses, and the physicians and nursing staff who were involved in patient care.

Author contributions

LS, FD, CH, MG, SS, HB and ML contributed to the design and analysis of this study; LS, TB and FD carried out laboratory-based analyses; LS, MG, HB and ML were involved in the care of patients; LS, HB and ML wrote this manuscript, and all authors contributed to and agreed on the final version.

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  1. H Becker and M Lübbert: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany

    L Solari, T Bauer, H Becker & M Lübbert

  2. MLL Munich Leukemia Laboratory, Munich, Germany

    F Dicker, C Haferlach & S Schnittger

  3. Department of Hematology and Oncology, Johannes Wesling Klinikum Minden, Minden, Germany

    M Grießhammer

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  1. L Solari
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Correspondence to M Lübbert.

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CH and SS declare part ownership of the MLL Munich Leukemia Laboratory GmbH. FD is employed by the MLL Munich Leukemia Laboratory GmbH.

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Solari, L., Bauer, T., Dicker, F. et al. A novel recurrent AML1–ETO fusion: tight in vivo association with BCR–ABL1. Leukemia 27, 1397–1400 (2013). https://doi.org/10.1038/leu.2013.53

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