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

AutorDovey, Oliver M.; Rad, Roland; Varela, Ignacio ; Vassiliou, George S.
Fecha de publicación2017
EditorAmerican Society of Hematology
CitaciónBlood 130(17): 1911-1922 (2017)
ResumenNPM1 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.
DescripciónDovey, Oliver M. et al.
Identificadoresdoi: 10.1182/blood-2017-01-760595
e-issn: 1528-0020
issn: 0006-4971
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