Sequentially Inducible Mouse Models Reveal That Npm1 Mutation Causes Malignant Transformation of Dnmt3a-Mutant Clonal Hematopoiesis

Details

• Alternative Title:
  Leukemia
• Personal Author:
  Loberg, Matthew A. ; Bell, Rebecca K. ; Goodwin, Leslie O. ; Eudy, Elizabeth ; Miles, Linde A. ; SanMiguel, Jennifer M. ; Young, Kira ; Bergstrom, David E. ; Levine, Ross L. ; Schneider, Rebekka K. ; Trowbridge, Jennifer J.
• Description:
  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.
• Subjects:
  Article
• Source:
  Leukemia. 33(7):1635-1649
• Pubmed ID:
  30692594
• Pubmed Central ID:
  PMC6609470
• Document Type:
  Journal Article
• Funding:
  U54 OD020355/ODCDC CDC HHS/Office of the Director/United States ; P30 AG038070/NIA NIH HHS/National Institute on Aging/United States ; T32 HD007065/NICHD NIH HHS/National Institute of Child Health & Human Development/United States ; P30 CA034196/NCI NIH HHS/National Cancer Institute/United States ; P30 CA008748/NCI NIH HHS/National Cancer Institute/United States ; R21 CA184851/NCI NIH HHS/National Cancer Institute/United States ; R35 CA197594/NCI NIH HHS/National Cancer Institute/United States ; R56 DK112947/NIDDK NIH HHS/National Institute of Diabetes and Digestive and Kidney Diseases/United States ; R01 DK118072/NIDDK NIH HHS/National Institute of Diabetes and Digestive and Kidney Diseases/United States ; R25 CA174584/NCI NIH HHS/National Cancer Institute/United States
• Volume:
  33
• Issue:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:f13604240c509144c4b2f2c960ad01f64c365ccec8dc5f7c7486edbfa443e15d
• Download URL:
  https://stacks.cdc.gov/view/cdc/80366/cdc_80366_DS1.pdf
• File Type:
  [PDF - 3.26 MB ]