MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells
MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells
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DOI：
10.1182/blood-2013-04-493858
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发表时间：
2014-01-30
期刊：
影响因子：
20.3
通讯作者：
Stone, Richard
中科院分区：
文献类型：
--
作者：
Liu, Suiyang;Yin, Li;Stone, Richard
大约三分之一的急性髓系白血病（AML）患者的原始细胞在FMS样酪氨酸激酶3（FLT 3）受体酪氨酸激酶中存在激活突变，导致预后不良。粘蛋白1-C-末端亚基（MUC 1-C）癌蛋白在AML母细胞和干细胞中异常表达;然而，MUC 1-C和FLT 3之间没有已知的相互作用。目前的研究表明，MUC 1-C与AML细胞中的野生型和突变型FLT 3相关。用细胞穿透肽抑制剂GO-203靶向MUC 1-C破坏MUC 1-C/FLT 3复合物并下调FLT 3活化。AML细胞的GO-203治疗也与FLT 3下游效应子AKT、细胞外信号调节激酶和STAT 5的抑制相关。结果进一步表明，具有FLT 3激活突变并对FLT 3抑制剂米多鲁肽/PKC 412具有抗性的AML细胞对GO-203诱导的生长停滞和死亡敏感。此外，GO-203增加突变型FLT 3 AML细胞对FLT 3抑制剂治疗的敏感性。这些结果表明，MUC 1-C有助于AML细胞中的FLT 3活化，并且靶向MUC 1-C抑制FLT 3信号传导途径。我们的研究结果支持开发MUC 1-C抑制剂单独使用以及与靶向FLT 3的药物联合使用，用于治疗野生型和突变型FLT 3 AML。
Blasts from approximately one-third of patients with acutemyeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells. Targeting MUC1-C with the cell-penetrating peptide inhibitor GO-203 disrupts MUC1-C/FLT3 complexes and downregulates FLT3 activation. GO-203 treatment of AML cells was also associated with inhibition of the FLT3 downstream effectors AKT, extracellular signal-regulated kinase, and STAT5. The results further show that AML cells with FLT3-activating mutations and resistant to the FLT3 inhibitor midostaurin/PKC412 are sensitive to GO-203-induced growth arrest and death. Moreover, GO-203 increases sensitivity of mutant FLT3 AML cells to FLT3 inhibitor treatment. These results indicate that MUC1-C contributes to FLT3 activation in AML cells and that targeting MUC1-C inhibits the FLT3 signaling pathway. Our findings support the development of MUC1-C inhibitors alone and in combination with agents that target FLT3 for the treatment of wild-type and mutant FLT3 AML.