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Blood. 2017 Oct 26;130(17):1911-1922. doi: 10.1182/blood-2017-01-760595. Epub 2017 Aug 23.

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

Author information

1
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
2
School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia.
3
PathWest Division of Clinical Pathology, Queen Elizabeth II Medical Centre, Nedlands, Australia.
4
Leukemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, London, United Kingdom.
5
Sample Phenotype Ontology Team, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom.
6
Institute of Translation, Innovation, Methodology, and Engagement, Cardiff University School of Medicine, Cardiff, United Kingdom.
7
Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
8
German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
9
Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
10
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom; and.
11
Instituto de Biomedicina y Biotecnología de Cantabria, Santander, Spain.

Abstract

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 2 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 overexpression, enhanced self-renewal, expansion of hematopoietic progenitors, and myeloid differentiation bias. However, Npm1cA;Flt3ITD mutants displayed significantly higher peripheral leukocyte counts, early depletion of common lymphoid progenitors, and a monocytic bias in comparison with 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 with 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 vs NPM1/NRAS-G12D-mutant AML and functionally confirm the role of HOXA genes in NPM1c-driven AML.

PMID:
28835438
PMCID:
PMC5672315
DOI:
10.1182/blood-2017-01-760595
[Indexed for MEDLINE]
Free PMC Article

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