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Ott1(Rbm15) Has Pleiotropic Roles in Hematopoietic Development

Glen D. Raffel, Thomas Mercher, Hirokazu Shigematsu, Ifor R. Williams, Dana E. Cullen, Koichi Akashi, Olivier A. Bernard and D. Gary Gilliland
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 14 (Apr. 3, 2007), pp. 6001-6006
Stable URL: http://www.jstor.org/stable/25427316
Page Count: 6
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Ott1(Rbm15) Has Pleiotropic Roles in Hematopoietic Development
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Abstract

OTT1(RBM15) was originally described as a 5' translocation partner of the MAL(MKL1) gene in t(1,22)(p13;q13) infant acute megakaryocytic 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 carboxylterminal) 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.

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