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

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 p...

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Bibliographic Details
Published in:	The Journal of clinical investigation Vol. 127; no. 10; pp. 3657 - 3674
Main Authors:	Cole, Christopher B., Russler-Germain, David A., Ketkar, Shamika, Verdoni, Angela M., Smith, Amanda M., Bangert, Celia V., Helton, Nichole M., Guo, Mindy, Klco, Jeffery M., O’Laughlin, Shelly, Fronick, Catrina, Fulton, Robert, Chang, Gue Su, Petti, Allegra A., Miller, Christopher A., Ley, Timothy J.
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01.10.2017
Subjects:	Academic libraries Acute myeloid leukemia Animals Bioinformatics Biomedical research Bone marrow Bone tumors Care and treatment Cell Line Cloning Deoxyribonucleic acid Diagnosis DNA DNA (Cytosine-5-)-Methyltransferases - genetics DNA methylation DNA methyltransferase Female Gene mutation Genetic Predisposition to Disease Genomes Haploinsufficiency Hematopoietic growth factors Hematopoietic stem cells Hematopoietic Stem Cells - enzymology Hematopoietic Stem Cells - pathology Humans Latent period Leukemia Leukemia, Myeloid, Acute - enzymology Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - pathology Male MAP kinase MAP Kinase Signaling System - genetics Methyltransferases Mice Mice, Mutant Strains Mutation Myeloid leukemia Point Mutation Proteins Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism Statistical analysis T cells Transplantation Tumors
ISSN:	0021-9738, 1558-8238, 1558-8238
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: C.B. Cole, D.A. Russler-Germain, and S. Ketkar contributed equally to this work.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI93041