Fms样酪氨酸激酶3
癌症研究
髓系白血病
白血病
生物
酪氨酸激酶
自磷酸化
信号转导
细胞生物学
免疫学
磷酸化
突变
遗传学
基因
蛋白激酶A
作者
Feng-Xian Zhai,Guozheng Pan,Lei Xue,Can Cheng,Jiabei Wang,Yao Liu,Lianxin Liu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-11-04
标识
DOI:10.1158/0008-5472.can-24-0577
摘要
Abstract Internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase-3 (FLT3) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with poor prognosis. FLT3-ITD mutations result in endoplasmic reticulum (ER) retention and constitutive autophosphorylation of FLT3. The PR/SET domain 16 (PRDM16) is highly expressed in FLT3-ITD+ AML patients, suggesting it might play a role in leukemogenesis. Here, we revealed that genetic and pharmacological suppression of PRDM16 greatly slowed the progression of FLT3-ITD-driven leukemia, sensitized leukemic cells to tyrosine kinase inhibitors (TKIs), and extended the survival of leukemic mice. PRDM16 enhanced activation of oncogenic FLT3-ITD and ligand-dependent activation of wild-type FLT3 in leukemic cells. Mechanistically, PRDM16 mediated monomethylation of FLT3-ITD at lysine 614 and promoted its ER localization, resulting in enhanced FLT3 signaling in leukemia cells. Moreover, pharmacological suppression of FLT3-ITD methylation in combination with TKIs increased the elimination of FLT3-ITD+ AML cells. Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.
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