Title is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsKunimoto, Hiroyoshi, McKenney Anna Sophia, Meydan Cem, Shank Kaitlyn, Nazir Abbas, Rapaport Franck, Durham Benjamin, Garrett-Bakelman Francine E., Pronier Elodie, Shih Alan H., Melnick Ari, Chaudhuri Jayanta, and Levine Ross L.
JournalBlood
Volume129
Issue13
Pagination1779-1790
Date Published2017 Mar 30
ISSN1528-0020
KeywordsAnimals, Cell Differentiation, Cell Lineage, Cell Self Renewal, Cell Transformation, Neoplastic, Cytidine Deaminase, Dioxygenases, DNA Methylation, DNA-Binding Proteins, Erythroid Cells, Gene Silencing, Hematopoietic Stem Cells, Humans, Mice, Myeloid Cells, Proto-Oncogene Proteins
Abstract

<p>Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of occur in myeloid malignancies, and hematopoietic-specific loss of induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of and , myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to loss, loss does not contribute to enhanced HSC self-renewal or cooperate with to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of as a key epigenetic regulator. These results indicate that and share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation.</p>

DOI10.1182/blood-2016-06-721977
Alternate JournalBlood
PubMed ID28077417
PubMed Central IDPMC5374286
Grant ListR01 CA198089 / CA / NCI NIH HHS / United States
R01 CA173636 / CA / NCI NIH HHS / United States
K08 CA169055 / CA / NCI NIH HHS / United States
R01 AI072194 / AI / NIAID NIH HHS / United States
R01 AI124186 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K08 CA181507 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
F30 CA183497 / CA / NCI NIH HHS / United States