4 years ago

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia.

Rad R, Vassiliou GS, Lynn C, Yusa K, Pacharne S, Vijayabaskar MS, Tzelepis K, Varela I, Mupo A, Grove CS, Bradley A, Cooper JL, Dovey OM, Wright P, Arends M, Andrews RM, Conte N, Green P
NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations we compare the effects of the two combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound Npm1cA/+;NrasG12D/+ or Npm1cA;Flt3ITD share a number of features: Hox gene over-expression, enhanced self-renewal, expansion of hematopoietic progenitors and myeloid differentiation bias. However, Npm1cA;Flt3ITD mutants, displayed significantly higher peripheral leucocyte counts, early depletion of common lymphoid progenitors and a monocytic bias compared to the granulocytic bias in Npm1cA/+;NrasG12D/+ mutants. Underlying this was a striking molecular synergy manifested as a dramatically altered gene expression profile in Npm1cA;Flt3ITD , but not Npm1cA/+;NrasG12D/+ , progenitors compared to wild type. Both double-mutant models developed high penetrance AML although latency was significantly longer with Npm1cA/+;NrasG12D/+ During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1cA/+;NrasG12D/+ mice showed acquisition of other human AML mutations, including IDH1 R132Q. We also find, using primary Cas9-expressing AMLs, that HoxA genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with NPM1c/FLT3-ITD versus NPM1/NRAS-G12D-mutant AML and functionally confirm the role of HOXA genes in NPM1-driven AML.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28835438

DOI: PubMed:28835438

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