title: Aidis a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells.
abstract: Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations ofTET2occur in myeloid malignancies, and hematopoietic-specific loss ofTet2induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicatingTET2as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role ofAIDloss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show thatAidloss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression ofCebpaandGata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing ofAIDin human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast toTet2loss,Aidloss does not contribute to enhanced HSC self-renewal or cooperate withFlt3-ITDto induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role ofAidas a key epigenetic regulator. These results indicate thatAIDandTET2share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation.
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kunimoto
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.|Gerstner Sloan Kettering Graduate School of Biomedical Sciences, and.|Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Anna Sophia
authors.initials: AS
authors.lastname: McKenney
authors.affiliation: Institute for Computational Biomedicine.|Department of Physiology and Biophysics, and.
authors.forename: Cem
authors.initials: C
authors.lastname: Meydan
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Shank
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.
authors.forename: Abbas
authors.initials: A
authors.lastname: Nazir
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.
authors.forename: Franck
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Durham
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Francine E
authors.initials: FE
authors.lastname: Garrett-Bakelman
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.
authors.forename: Elodie
authors.initials: E
authors.lastname: Pronier
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.|Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Shih
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY.|Department of Pharmacology, Weill Cornell Medical College, New York, NY; and.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
authors.affiliation: Human Oncology and Pathogenesis Program.|Center for Epigenetics Research.|Center for Hematologic Malignancies.|Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D000066673:Cell Self Renewal; D002471:Cell Transformation, Neoplastic; D003564:Cytidine Deaminase / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D049308:Dioxygenases; D041905:Erythroid Cells / Q000166:cytology; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; C551914:Tet2 protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase