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Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies
Christopher B. Cole, … , Christopher A. Miller, Timothy J. Ley
Christopher B. Cole, … , Christopher A. Miller, Timothy J. Ley
Published September 5, 2017
Citation Information: J Clin Invest. 2017;127(10):3657-3674. https://doi.org/10.1172/JCI93041.
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Research Article Hematology Oncology

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

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Abstract

The gene that encodes de novo DNA methyltransferase 3A (DNMT3A) is frequently mutated in acute myeloid leukemia genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins that could either have dominant negative activities or cause loss of function and haploinsufficiency. Here, we demonstrate that 3 of these mutants produce truncated, inactive proteins that do not dimerize with WT DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation. With no other manipulations, Dnmt3a+/– mice developed myeloid skewing over time, and their hematopoietic stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/– mice also spontaneously developed transplantable myeloid malignancies after a long latent period, and 3 of 12 tumors tested had cooperating mutations in the Ras/MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in these tumors. The bone marrow cells of Dnmt3a+/– mice had a subtle but statistically significant DNA hypomethylation phenotype that was not associated with gene dysregulation. These data demonstrate that haploinsufficiency for Dnmt3a alters hematopoiesis and predisposes mice (and probably humans) to myeloid malignancies by a mechanism that is not yet clear.

Authors

Christopher B. Cole, David A. Russler-Germain, Shamika Ketkar, Angela M. Verdoni, Amanda M. Smith, Celia V. Bangert, Nichole M. Helton, Mindy Guo, Jeffery M. Klco, Shelly O’Laughlin, Catrina Fronick, Robert Fulton, Gue Su Chang, Allegra A. Petti, Christopher A. Miller, Timothy J. Ley

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Figure 4

Bone marrow cells from Dnmt3a+/– mice display myeloid skewing and a competitive advantage that is time dependent.

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Bone marrow cells from Dnmt3a+/– mice display myeloid skewing and a comp...
(A and B) Flow cytometric evaluation of lineage markers from the bone marrow cells of unmanipulated mice harvested at the indicated ages, designated in months (n = 1 per genotype per time point). (A) Dnmt3a+/+ mice. (B) Dnmt3a+/– mice. (C–G) Bone marrow from 6-week-old Dnmt3a+/+ or Dnmt3a+/– mice (Ly5.2) was mixed 50:50 with WT competitor marrow (Ly5.1x5.2) and transplanted into lethally irradiated WT mice (Ly5.1). n = 13 Dnmt3a+/+; n = 10 Dnmt3a+/–. (C) Peripheral blood chimerism at 4 months, 6 months, and 1 year after transplant. P < 0.01, 2-sample, 2-tailed t test. (D–G) Percentage of Ly5.2+ cells (i.e., experimental cells, either Dnmt3a+/+ or Dnmt3a+/–) in the indicated lineage or progenitor populations at the 1-year time point. *P < 0.05, 1-sample, 2-tailed t test vs. 50% corrected for multiple testing by Bonferroni’s method. (D) Peripheral blood–derived cells. (E) Spleen-derived cells. (F and G) Bone marrow–derived cells.
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