Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis Journal Article

   

Authors:	Loberg, M. A.; Bell, R. K.; Goodwin, L. O.; Eudy, E.; Miles, L. A.; SanMiguel, J. M.; Young, K.; Bergstrom, D. E.; Levine, R. L.; Schneider, R. K.; Trowbridge, J. J.
Article Title:	Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis
Abstract:	Clonal hematopoiesis (CH) is a common aging-associated condition with increased risk of hematologic malignancy. Knowledge of the mechanisms driving evolution from CH to overt malignancy has been hampered by a lack of in vivo models that orthogonally activate mutant alleles. Here, we develop independently regulatable mutations in DNA methyltransferase 3A (Dnmt3a) and nucleophosmin 1 (Npm1), observed in human CH and AML, respectively. We find Dnmt3a mutation expands hematopoietic stem and multipotent progenitor cells (HSC/MPPs), modeling CH. Induction of mutant Npm1 after development of Dnmt3a-mutant CH causes progression to myeloproliferative disorder (MPD), and more aggressive MPD is observed with longer latency between mutations. MPDs uniformly progress to acute myeloid leukemia (AML) following transplant, accompanied by a decrease in HSC/MPPs and an increase in myeloid-restricted progenitors, the latter of which propagate AML in tertiary recipient mice. At a molecular level, progression of CH to MPD is accompanied by selection for mutations activating Ras/Raf/MAPK signaling. Progression to AML is characterized by additional oncogenic signaling mutations (Ptpn11, Pik3r1, Flt3) and/or mutations in epigenetic regulators (Hdac1, Idh1, Arid1a). Together, our study demonstrates that Npm1 mutation drives evolution of Dnmt3a-mutant CH to AML and rate of disease progression is accelerated with longer latency of CH. © 2019, The Author(s).
Journal Title:	Leukemia
Volume:	33
Issue:	7
ISSN:	0887-6924
Publisher:	Nature Publishing Group
Date Published:	2019-07-01
Start Page:	1635
End Page:	1649
Language:	English
DOI:	10.1038/s41375-018-0368-6
PUBMED:	30692594
PROVIDER:	scopus
PMCID:	PMC6609470
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060821128&doi=10.1038%2fs41375-018-0368-6&partnerID=40&md5=3319235fb96ab6459448f4edbe3fd8f9
Notes:	Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/150331