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Acute myeloid leukemia

Subtype-specific patterns of molecular mutations in acute myeloid leukemia

Leukemia volume 31, pages 11–17 (2017)Cite this article

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Abstract

Acute myeloid leukemia (AML) can be grouped into morphologically or genetically defined subtypes. Today, the AML phenotype–genotype associations, that is, FAB/WHO (French–American–British/World Health Organization) definitions and recurrent molecular mutations, are not fully understood. Therefore, we evaluated the impact of molecular mutations on the AML differentiation stage by molecular profiling of 4373 adult de novo AML patients in 7 cytomorphological subtypes. We investigated mutations in 20 genes, including myeloid transcription factors (CEBPA, RUNX1), tumor suppressors (TP53, WT1), DNA modifiers (DNMT3A, IDH1/2, TET2), chromatin modifiers (ASXL1, MLL), signal transduction genes (FLT3, KRAS, NRAS) and NPM1. The most frequently mutated genes per cytomorphological subtype were RUNX1 in M0 (43%), NPM1 in M1 (42%), DNMT3A in M2 (26%), NPM1 in M4 (57%), M5a (49%) and M5b (70%) and TP53 in M6 (36%). Although some gene mutations were frequent in several cytomorphological subtypes, a series of associations of co-occurring mutations with distinct phenotypes were identified for molecularly defined subcohorts. FLT3, NPM1 and WT1 mutations were associated with an immature phenotype in myeloblastic AML, whereas other combinations involving ASXL1, RUNX1, MLL-PTD, CEBPA or KRAS were more frequent in myeloblastic AML with maturation. Within the NPM1 mutated subcohort, ASXL1 mutations were significantly associated with a monoblastic differentiation and DNMT3A mutations with a monocytic phenotype.

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Acknowledgements

We thank all the co-workers in our laboratory for their excellent technical assistance and all clinicians for sending samples to our laboratory for diagnostic purposes, and for providing clinical information and follow-up data

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Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Munich, Germany

    D Rose, T Haferlach, S Schnittger, W Kern & C Haferlach

  2. MLL2 s.r.o., Prague, Czech Republic

    K Perglerová

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Correspondence to C Haferlach.

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Competing interests

TH, WK and CH have equity ownership of the MLL Munich Leukemia Laboratory GmbH. DR and KP are employed by the MLL Munich Leukemia Laboratory GmbH and the MLL2 s.r.o., respectively.

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Rose, D., Haferlach, T., Schnittger, S. et al. Subtype-specific patterns of molecular mutations in acute myeloid leukemia. Leukemia 31, 11–17 (2017). https://doi.org/10.1038/leu.2016.163

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