title: Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl.
abstract: Thrombopoietin (Thpo) signaling through the c-Mpl receptor promotes either quiescence or proliferation of hematopoietic stem cells (HSCs) in a concentration-dependent manner; however, in vivo Thpo serum levels are responsive to platelet mass rather than HSC demands, suggesting additional regulation exists. Ott1 (Rbm15), a spliceosomal component originally identified as a fusion partner in t(1;22)-associated acute megakaryocytic leukemia, is also essential for maintaining HSC quiescence under stress. Ott1 controls the alternative splicing of a dominant negative isoform, Mpl-TR, capable of inhibiting HSC engraftment and attenuating Thpo signaling. Ott1, which associates with Hdac3 and the histone methyltransferase, Setd1b, binds to both c-Mpl RNA and chromatin and regulates H4 acetylation and H3K4me3 marks. Histone deacetylase or histone methyltransferase inhibition also increases Mpl-TR levels, suggesting that Ott1 uses an underlying epigenetic mechanism to control alternative splicing of c-Mpl. Manipulation of Ott1-dependent alternative splicing may therefore provide a novel pharmacologic avenue for regulating HSC quiescence and proliferation in response to Thpo.
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA; and.
authors.forename: Nan
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA; and.
authors.forename: Suparna
authors.initials: S
authors.lastname: Laha
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA; and.
authors.forename: Shankar P
authors.initials: SP
authors.lastname: Das
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA; and.
authors.forename: Kayla
authors.initials: K
authors.lastname: Morlock
authors.affiliation: Essess, Inc., Boston, MA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Jesneck
authors.affiliation: Division of Hematology-Oncology, University of Massachusetts Medical School, Worcester, MA; and.
authors.forename: Glen D
authors.initials: GD
authors.lastname: Raffel
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053628:Receptors, Thrombopoietin / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction; D013926:Thrombopoietin / Q000378:metabolism*
chemical_list: D002843:Chromatin; C481270:Mpl protein, mouse; D020033:Protein Isoforms; C431574:RBM15 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C519408:Rbm15 protein, mouse; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin