Hematopoiesis and stem cells: Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation

Allison Mayle, Liubin Yang, Benjamin Rodriguez, Ting Zhou, Edmund Chang, Choladda V. Curry, Grant A. Challen, Wei Li, David Wheeler, Vivienne I. Rebel, Margaret A. Goodell

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

DNA methyltransferase 3A (DNMT3A) is mutated in hematologic malignancies affecting myeloid, mixed, and lymphoid lineages, and these mutations are associated with poor prognosis. Past studies in mice revealed Dnmt3a-knockout (KO)hematopoieticstem cells (HSCs) had increased self-renewal, but no leukemia was observed. Here, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 year. Animals were diagnosed with a spectrum of malignancies similar to those seen in patients withDNMT3A mutations, including myelodysplastic syndrome, acute myeloid leukemia, primary myelofibrosis, and T- and B-cell acute lymphocytic leukemia. In some cases, acquired malignancies exhibited secondarymutations similar to those identified in patients. Loss of Dnmt3a led to disturbed methylation patterns that were distinct in lymphoid and myeloid disease, suggesting lineage-specific methylation aberrations promoted by Dnmt3a loss. Global hypomethylation was observed in all of the malignancies, but lymphoid malignancies also exhibited hypermethylation, particularly at promoter regions. This mousemodel underscores the important role ofDnmt3a in normal hematopoietic development and demonstrates that Dnmt3a loss of function confers a preleukemic phenotype on murine HSCs. This model may serve as a tool to study DNMT3A mutation-associated malignancies and for developing targeted strategies for eliminating preleukemic cells for prevention and treatment of hematologic malignancies in the future.

Original languageEnglish (US)
Pages (from-to)629-638
Number of pages10
JournalBlood
Volume125
Issue number4
DOIs
StatePublished - Jan 22 2015

Fingerprint

Hematopoiesis
Hematopoietic Stem Cells
Stem cells
Methylation
Stem Cells
Hematologic Neoplasms
Neoplasms
Mutation
Aberrations
Genetic Promoter Regions
Biphenotypic Acute Leukemia
Animals
Primary Myelofibrosis
Cells
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Leukemia
Phenotype
DNA methyltransferase 3A

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Mayle, A., Yang, L., Rodriguez, B., Zhou, T., Chang, E., Curry, C. V., ... Goodell, M. A. (2015). Hematopoiesis and stem cells: Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood, 125(4), 629-638. https://doi.org/10.1182/blood-2014-08-594648

Hematopoiesis and stem cells : Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. / Mayle, Allison; Yang, Liubin; Rodriguez, Benjamin; Zhou, Ting; Chang, Edmund; Curry, Choladda V.; Challen, Grant A.; Li, Wei; Wheeler, David; Rebel, Vivienne I.; Goodell, Margaret A.

In: Blood, Vol. 125, No. 4, 22.01.2015, p. 629-638.

Research output: Contribution to journalArticle

Mayle, A, Yang, L, Rodriguez, B, Zhou, T, Chang, E, Curry, CV, Challen, GA, Li, W, Wheeler, D, Rebel, VI & Goodell, MA 2015, 'Hematopoiesis and stem cells: Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation', Blood, vol. 125, no. 4, pp. 629-638. https://doi.org/10.1182/blood-2014-08-594648
Mayle, Allison ; Yang, Liubin ; Rodriguez, Benjamin ; Zhou, Ting ; Chang, Edmund ; Curry, Choladda V. ; Challen, Grant A. ; Li, Wei ; Wheeler, David ; Rebel, Vivienne I. ; Goodell, Margaret A. / Hematopoiesis and stem cells : Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. In: Blood. 2015 ; Vol. 125, No. 4. pp. 629-638.
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