TitleDNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.
Publication TypeJournal Article
Year of Publication2016
AuthorsMeyer, Sara E., Qin Tingting, Muench David E., Masuda Kohei, Venkatasubramanian Meenakshi, Orr Emily, Suarez Lauren, Gore Steven D., Delwel Ruud, Paietta Elisabeth, Tallman Martin S., Fernandez Hugo, Melnick Ari, Le Beau Michelle M., Kogan Scott, Salomonis Nathan, Figueroa Maria E., and H Grimes Leighton
JournalCancer Discov
Date Published2016 May
KeywordsAnimals, Biopsy, Bone Marrow, Cell Transformation, Neoplastic, Cluster Analysis, Disease Models, Animal, Disease Progression, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA Methyltransferase 3A, fms-Like Tyrosine Kinase 3, Gene Expression Profiling, Gene Expression Regulation, Genetic Loci, Genotype, Haploinsufficiency, High-Throughput Nucleotide Sequencing, Humans, Karyotype, Leukemia, Myeloid, Acute, Mice, Mice, Transgenic, Mutation, Myeloproliferative Disorders, Penetrance, Tandem Repeat Sequences

<p><b>UNLABELLED: </b>Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3(ITD)/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.</p><p><b>SIGNIFICANCE: </b>DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.</p>

Alternate JournalCancer Discov
PubMed ID27016502
PubMed Central IDPMC4861898
Grant ListR01 CA159845 / CA / NCI NIH HHS / United States
T32 ES007250 / ES / NIEHS NIH HHS / United States
U01 HL099997 / HL / NHLBI NIH HHS / United States
U24 CA196172 / CA / NCI NIH HHS / United States
R01 CA196658 / CA / NCI NIH HHS / United States
UL1 TR001425 / TR / NCATS NIH HHS / United States
U10 CA180820 / CA / NCI NIH HHS / United States
T32 GM008752 / GM / NIGMS NIH HHS / United States
R21 CA186945 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States