title: Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling.
abstract: The transcription factor Ikaros regulates the development of hematopoietic cells. Ikaros-deficient animals fail to develop B cells and display a T-cell malignancy, which is correlated with altered Notch signaling. Recently, loss of Ikaros was associated with progression of myeloproliferative neoplasms to acute myeloid leukemia and increasing evidence shows that Ikaros is also critical for the regulation of myeloid development. Previous studies showed that Ikaros-deficient mice have increased megakaryopoiesis, but the molecular mechanism of this phenomenon remains unknown. Here, we show that Ikaros overexpression decreases NOTCH-induced megakaryocytic specification, and represses expression of several megakaryocytic genes including GATA-1 to block differentiation and terminal maturation. We also demonstrate that Ikaros expression is differentially regulated by GATA-2 and GATA-1 during megakaryocytic differentiation and reveal that the combined loss of Ikzf1 and Gata1 leads to synthetic lethality in vivo associated with prominent defects in erythroid cells and an expansion of megakaryocyte progenitors. Taken together, our observations demonstrate an important functional interplay between Ikaros, GATA factors, and the NOTCH signaling pathway in specification and homeostasis of the megakaryocyte lineage.
authors: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA.
authors: Sébastien
authors: S
authors: Malinge
authors: Clarisse
authors: C
authors: Thiollier
authors: Timothy M
authors: TM
authors: Chlon
authors: Louis C
authors: LC
authors: Doré
authors: Lauren
authors: L
authors: Diebold
authors: Olivier
authors: O
authors: Bluteau
authors: Vinciane
authors: V
authors: Mabialah
authors: William
authors: W
authors: Vainchenker
authors: Philippe
authors: P
authors: Dessen
authors: Susan
authors: S
authors: Winandy
authors: Thomas
authors: T
authors: Mercher
authors: John D
authors: JD
authors: Crispino
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D004622:Embryo, Mammalian; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008533:Megakaryocytes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D034061:Thrombopoiesis / Q000235:genetics*
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D051880:Receptors, Notch; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor