TitleGenetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis.
Publication TypeJournal Article
Year of Publication2018
AuthorsPronier, Elodie, Bowman Robert L., Ahn Jihae, Glass Jacob, Kandoth Cyriac, Merlinsky Tiffany R., Whitfield Justin T., Durham Benjamin H., Gruet Antoine, Somasundara Amritha Varshini H., Rampal Raajit, Melnick Ari, Koche Richard P., Taylor Barry S., and Levine Ross L.
JournalBlood
Volume132
Issue12
Pagination1265-1278
Date Published2018 09 20
ISSN1528-0020
KeywordsAnimals, Carcinogenesis, Cell Self Renewal, Epigenesis, Genetic, fms-Like Tyrosine Kinase 3, Gene Deletion, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Leukemia, Myeloid, Acute, Leukopoiesis, Mice, Inbred C57BL, Mice, Knockout, Mutation, Myeloid Cells, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Repressor Proteins, WT1 Proteins
Abstract

<p>Genetic studies have identified recurrent somatic mutations in acute myeloid leukemia (AML) patients, including in the Wilms' tumor 1 () gene. The molecular mechanisms by which mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of gene dosage in steady-state and pathologic hematopoiesis. heterozygous loss enhanced stem cell self-renewal in an age-dependent manner, which increased stem cell function over time and resulted in age-dependent leukemic transformation. -haploinsufficient leukemias were characterized by progressive genetic and epigenetic alterations, including those in known leukemia-associated alleles, demonstrating a requirement for additional events to promote hematopoietic transformation. Consistent with this observation, we found that depletion cooperates with mutation to induce fully penetrant AML. Our studies provide insight into mechanisms of -loss leukemogenesis and into the evolutionary events required to induce transformation of -haploinsufficient stem/progenitor cells.</p>

DOI10.1182/blood-2018-03-837468
Alternate JournalBlood
PubMed ID30064973
PubMed Central IDPMC6148447
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R35 CA197594 / CA / NCI NIH HHS / United States
U54 OD020355 / OD / NIH HHS / United States