Ott1(Rbm15) has pleiotropic roles in hematopoietic development
Ott1(Rbm15) has pleiotropic roles in hematopoietic development
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DOI：
10.1073/pnas.0609041104
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发表时间：
2007-04-03
影响因子：
11.1
通讯作者：
Gilliland, D. Gary
中科院分区：
文献类型：
--
作者：
Raffel, Glen D.;Mercher, Thomas;Gilliland, D. Gary
OTT 1（RBM 15）最初被描述为t（1，22）（p13;q13）婴儿急性巨核细胞白血病中MAL（MKL 1）基因的5'易位伴侣。OTT 1没有确定的生理功能，但它与spen/Mint/SHARP蛋白家族具有同源性，该蛋白家族由三个氨基末端RNA识别基序和一个羧基末端SPOC（Spen parthaloma and ortholog carboxyl-terminal）结构域定义，据信该结构域可作为转录抑制因子。为了明确OTT 1在造血中的作用并帮助阐明t（1，22）急性巨核细胞白血病的发病机制，在小鼠中产生了OTT 1的条件等位基因。在成年小鼠中，由于阻断了前/前B分化，缺失了CD 45 1导致外周B细胞的损失。脾和骨髓中存在髓样和巨核细胞扩增，包括造血干细胞的Lin（-）Sca-1（+）c-Kit（+）区室增加，以及祖细胞命运向粒细胞分化的转变。这些数据表明，在B淋巴细胞生成中需要BMP 1，并且在骨髓、巨核细胞和祖细胞隔室中具有抑制作用。在多个谱系中影响造血细胞命运和扩增的能力是spen家族成员的一个新属性，并将spen 1与其他已知的造血发育效应子区分开来。这似乎是合理的，OTT 1-MAL依赖的造血发育途径的失调，特别是那些影响巨核细胞谱系，可能有助于OTT 1-MAL介导的白血病发生。
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 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.