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High incidence of RAS signalling pathway mutations in MLL-rearranged acute myeloid leukemia

Leukemia volume 27, pages 1933–1936 (2013)Cite this article

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Chromosomal translocations of the MLL H3K4 histone methyltransferase gene on chromosome 11q23 are associated with unique subsets of both acute lymphoblastic (ALL) and acute myeloid leukemias (AML).1 The MLL gene encodes for a large protein of 3969 amino acids and has a role in chromatin-mediated transcriptional regulation.2 Translocations of chromosome 11q23 usually result in a chimeric fusion gene retaining the N-terminal part of the MLL gene fused to a C-terminal partner gene, which acts to transform normal hematopoietic cells.3 In adults, MLL rearrangements are detected in 3% of de novo AML and in 10% of therapy-related AML (t-AML) cases, and are associated with an aggressive course of disease and poor prognosis.3 Recently, high-throughput sequencing studies had shown that in addition to disease defining mutations almost all myeloid malignancies accumulate a large number of cooperating gene mutations.4 Therefore, we here investigated the occurrence and prognostic impact of somatic mutations in adult AML cases harboring MLL rearrangements.

Bone marrow and peripheral blood specimens of 4686 de novo AML and 313 t-AML cases, sent for diagnosis to the MLL Munich Leukemia Laboratory between 08/2005 and 11/2012, were included. Within this unselected cohort translocations involving chromosome 11q23 were identified by chromosome banding analysis in 134 de novo and 53 t-AML cases. All MLL rearrangements were verified by fluorescence in situ hybridization and/or reverse transcriptase PCR (RT-PCR), resulting in a frequency of 2.8% and 14.5%, respectively. On the basis of the availability of specimens for further analyses, a total cohort of 118 adult AML cases was selected (85 de novo, 33 t-AML) for subsequent molecular studies. The cohort was composed of 72 female and 46 male patients, and the median age was 53.3 years (range: 19.3–83.5 years). Additional clinical data and information on the fusion partner genes are depicted in Table 1. Further, survival data were available in 94 cases (median overall survival (OS) was 16.2 months). OS and event-free survival (EFS) did not differ between de novo and t-AML cases (median OS: 16.7 vs 12.1 months, P=0.461; median EFS: 9.2 vs 9.8 months, P=0.948).

Table 1 Clinical characteristics of the patient cohort and %EVI1/ABL1 level
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Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Munich, Germany

    V Grossmann, S Schnittger, F Poetzinger, A Kohlmann, A Stiel, C Eder, A Fasan, W Kern, T Haferlach & C Haferlach

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  1. V Grossmann
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  2. S Schnittger
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  8. W Kern
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Correspondence to C Haferlach.

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Competing interests

CH, SS, WK and TH have equity ownership of Munich Leukemia Laboratory (MLL). VG, FP, AK, AS, CE and AF are employed by MLL.

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Grossmann, V., Schnittger, S., Poetzinger, F. et al. High incidence of RAS signalling pathway mutations in MLL-rearranged acute myeloid leukemia. Leukemia 27, 1933–1936 (2013). https://doi.org/10.1038/leu.2013.90

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