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

Oliver M. Dovey, Jonathan L. Cooper, Annalisa Mupo, Carolyn S. Grove, Claire Lynn, Nathalie Conte, Robert M. Andrews, Suruchi Pacharne, Konstantinos Tzelepis, M. S. Vijayabaskar, Paul Green, Roland Rad, Mark Arends, Penny Wright, Kosuke Yusa, Allan Bradley, Ignacio Varela, George S. Vassiliou

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandemduplications (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 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis showthatcompoundNpm1cA/1;NrasG12D/1orNpm1cA;Flt3ITD share anumber of features:Hox gene overexpression, enhancedself-renewal, expansionof hematopoietic progenitors,and myeloid differentiation bias. However, Npm1cA;Flt3ITD mutants displayed significantly higherperipheral leukocytecounts, earlydepletionofcommonlymphoidprogenitors, anda monocytic bias in comparison with the granulocytic bias in Npm1cA/1;NrasG12D/1 mutants. Underlying thiswas a strikingmolecular synergymanifested as a dramatically altered gene expression profile in Npm1cA;Flt3ITD, but not Npm1cA/1;NrasG12D/1, progenitors compared with wild-type. Both double-mutant models developed high-penetrance AML, although latency was significantly longer with Npm1cA/1;NrasG12D/1. During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1cA/1;NrasG12D/1 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 vs NPM1/NRASG12D-mutant AML and functionally confirm the role of HOXA genes in NPM1c-driven AML.

Original languageEnglish
Pages (from-to)1911-1922
Number of pages12
JournalBlood
Volume130
Issue number17
DOIs
Publication statusPublished - 26 Oct 2017

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