Identification and targeting of novel CDK9 complexes in acute myeloid leukemia
Identification and targeting of novel CDK9 complexes in acute myeloid leukemia
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DOI：
10.1182/blood-2018-08-870089
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发表时间：
2019-03-14
期刊：
影响因子：
20.3
通讯作者：
Platanias, Leonidas C.
中科院分区：
文献类型：
--
作者：
Beauchamp, Elspeth M.;Abedin, Sameem M.;Platanias, Leonidas C.
急性髓细胞白血病（AML）中mTOR信号传导的异常激活导致促进恶性表型的生存优势。为了提高我们对哺乳动物雷帕霉素靶蛋白（mTOR）信号转导激活因子的理解，并确定新的治疗靶点，我们通过蛋白质组学分析寻找mTOR复合物的独特相互作用物。我们确定细胞周期蛋白依赖性激酶9（CDK9）作为mTOR复合物支架蛋白mLST 8的新结合伴侣。我们的研究表明，CDK9存在于不同的mTOR样（CTOR）复合物中的细胞质和细胞核。在细胞核中，CDK9与RAPTOR和mLST 8结合，形成CTORC1，以促进对白血病发生重要的基因的转录。在细胞质中，CDK9与RICTOR、SIN 1和mLST 8结合，形成CTORC2，并通过LARP 1和rpS6的磷酸化控制信使RNA（mRNA）翻译。CTORC复合物的药理学靶向导致体外原始人AML祖细胞的生长抑制，并在体内AML异种移植物中引起强烈的抗白血病应答。
Aberrant activation of mTOR signaling in acute myeloid leukemia (AML) results in a survival advantage that promotes the malignant phenotype. To improve our understanding of factors that contribute to mammalian target of rapamycin (mTOR) signaling activation and identify novel therapeutic targets, we searched for unique interactors of mTOR complexes through proteomics analyses. We identify cyclin dependent kinase 9 (CDK9) as a novel binding partner of the mTOR complex scaffold protein, mLST8. Our studies demonstrate that CDK9 is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and nucleus. In the nucleus, CDK9 binds to RAPTOR and mLST8, forming CTORC1, to promote transcription of genes important for leukemogenesis. In the cytoplasm, CDK9 binds to RICTOR, SIN1, and mLST8, forming CTORC2, and controls messenger RNA (mRNA) translation through phosphorylation of LARP1 and rpS6. Pharmacological targeting of CTORC complexes results in suppression of growth of primitive human AML progenitors in vitro and elicits strong antileukemic responses in AML xenografts in vivo.