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| Status |
Public on Aug 01, 2017 |
| Title |
DNMT3A haploinsufficiency predisposes hematopoietic cells to myeloid malignancies |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
DNMT3A (which encodes a de novo DNA methyltransferase) is one of the most frequently mutated genes in AML 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, which could either have dominant negative activities, or cause loss-of-function and haploinsufficiency. We demonstrate that three of these mutants produce truncated, inactive proteins that do not dimerize with wild-type DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation: unmanipulated mice developed myeloid skewing over time, and their stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/- mice spontaneously developed transplantable myeloid malignancies after a long latent period, and three of 12 tumors tested had cooperating mutations in the Ras- MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in tumors. The bone marrow cells of Dnmt3a+/- mice had a subtle but 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.
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| |
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| Overall design |
Mouse Microarray
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| |
|
| Contributor(s) |
Cole C, Russler-Germain D, Ketkar S, Ley TJ |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Jun 30, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Timothy J Ley |
| Organization name |
Washington University School of Medicine
|
| Department |
Internal Medicine
|
| Street address |
660 S Euclid Avenue
|
| City |
St Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL6193 |
[MoEx-1_0-st] Affymetrix Mouse Exon 1.0 ST Array [probe set (exon) version] |
|
| Samples (6)
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| Relations |
| BioProject |
PRJNA392688 |
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