title: Ott1(Rbm15) has pleiotropic roles in hematopoietic development.
abstract: OTT1(RBM15) was originally described as a 5' translocation partner of the MAL(MKL1) gene in t(1,22)(p13;q13) infant acute mega karyocytic leukemia. OTT1 has no established physiological function, but it shares homology with the spen/Mint/SHARP family of proteins defined by three amino-terminal RNA recognition motifs and a carboxyl-terminal SPOC (Spen paralog and ortholog carboxyl-terminal) domain believed to act as a transcriptional repressor. To define the role of OTT1 in hematopoiesis and help elucidate the mechanism of t(1,22) acute megakaryocytic leukemia pathogenesis, a conditional allele of Ott1 was generated in mice. Deletion of Ott1 in adult mice caused a loss of peripheral B cells due to a block in pro/pre-B differentiation. There is myeloid and megakaryocytic expansion in spleen and bone marrow, an increase in the Lin(-)Sca-1(+)c-Kit(+) compartment that includes hematopoietic stem cells, and a shift in progenitor fate toward granulocyte differentiation. These data show a requirement for Ott1 in B lymphopoiesis, and inhibitory roles in the myeloid, megakaryocytic, and progenitor compartments. The ability of Ott1 to affect hematopoietic cell fate and expansion in multiple lineages is a novel attribute for a spen family member and delineates Ott1 from other known effectors of hematopoietic development. It is plausible that dysregulation of Ott1-dependent hematopoietic developmental pathways, in particular those affecting the megakaryocyte lineage, may contribute to OTT1-MAL-mediated leukemogenesis.
authors: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. graffel@bidmc.harvard.edu
authors: Glen D
authors: GD
authors: Raffel
authors: Thomas
authors: T
authors: Mercher
authors: Hirokazu
authors: H
authors: Shigematsu
authors: Ifor R
authors: IR
authors: Williams
authors: Dana E
authors: DE
authors: Cullen
authors: Koichi
authors: K
authors: Akashi
authors: Olivier A
authors: OA
authors: Bernard
authors: D Gary
authors: DG
authors: Gilliland
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D019070:Cell Lineage; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology*; D006413:Hematopoietic System / Q000502:physiology*; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology
chemical_list: D029721:Drosophila Proteins; D016601:RNA-Binding Proteins; C519408:Rbm15 protein, mouse