@article{10902/12979,
year = {2017},
month = {10},
url = {http://hdl.handle.net/10902/12979},
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.},
publisher = {American Society of Hematology},
publisher = {Blood. 2017 Oct 26;130(17):1911-1922},
title = {Molecular synergy underlies the co-occurrence patterns and phenotype 
of NPM1-mutant acute myeloid leukemia},
author = {Dovey, Oliver M. and Cooper, Jonathan L. and Mupo, Annalisa and Grove, Carolyn S. and Lynn, Claire and Conte, Nathalie and Andrews, Robert M. and Pacharne, Suruchi and Tzelepis, Konstantinos and Vijayabaskar, M. S. and Green, Paul and Rad, Roland and Arends, Mark and Wright, Penny and Yusa, Kosuke and Bradley, Allan and Varela Egocheaga, Ignacio and Vassiliou, George S.},
}