Ott1(Rbm15) Is Essential for Pre-B Differentiation and Has an Inhibitory Role in Myeloid and Megakaryocytic Lineages.

OTT1(RBM15) is a putative transcriptional repressor related to the spen/Mint/SHARP family of proteins which was originally identified as the 5′ translocation partner of the MAL(MKL1) gene in t(1;22)(p13;q13) infant acute megakaryocytic leukemia (AMKL). OTT1 contains RNA recognition motifs (RRMs) and a transactivation/repression spen paralog and ortholog (SPOC) homology domain however no physiologic function has yet been attributed to it. To define the role of OTT1 in hematopoiesis and help gain an understanding of potential dysregulated pathways in t(1;22) AMKL, a conditional allele of Ott1 was generated in mice. Germline deletion of Ott1 was early embryonic lethal, however, deletion in adult mice utilizing the Mx1-Cre transgene affected multiple lineages within the hematopoietic compartment. Deletion of Ott1 caused a loss of peripheral B cells as a result of block in pro/pre-B differentiation. An expansion myeloid cells was seen in the spleen and bone marrow and increased numbers of myeloid CFU were detected in the bone marrow. Progenitor analysis demonstrated in increase in Lin⁻Sca-1⁺c-Kit⁺ (LSK) cells with an altered clonogenicity shifting towards granulocytic cell fate. Finally, increased numbers of megakaryocytes were found in the bone marrow and spleen suggesting a negative role for Ott1 in megakaryocytic proliferation/survival. These data indicate a requirement for Ott1 in B lymphopoiesis and inhibitory roles within the myeloid, megakaryocytic and progenitor compartments. Accordingly, the ability of Ott1 to affect hematopoietic cell fate and expansion within multiple lineages including megakaryocytes may underlie the mechanism of OTT1-MAL-mediated leukemogenesis.