PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression.

IF 12.5 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2024-11-04 DOI:10.1158/0008-5472.CAN-24-0577

Fengxian Zhai, Guozheng Pan, Lei Xue, Can Cheng, Jiabei Wang, Yao Liu, Lianxin Liu

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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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PRDM16 诱导 FLT3 甲基化，促进 FLT3-ITD 信号转导和白血病进展

FMS样受体酪氨酸激酶-3（FLT3）的内部串联重复（ITD）是急性髓性白血病（AML）中最常见的突变之一，与预后不良有关。FLT3-ITD突变导致内质网（ER）滞留和FLT3组成性自磷酸化。PR/SET结构域16（PRDM16）在FLT3-ITD+ AML患者中高表达，表明它可能在白血病发生中发挥作用。在这里，我们发现遗传和药物抑制 PRDM16 可大大减缓 FLT3-ITD 驱动的白血病的进展，使白血病细胞对酪氨酸激酶抑制剂（TKIs）敏感，并延长白血病小鼠的存活时间。PRDM16 增强了白血病细胞中致癌 FLT3-ITD 的活化和野生型 FLT3 的配体依赖性活化。从机理上讲，PRDM16介导了FLT3-ITD赖氨酸614处的单甲基化，并促进了其ER定位，从而增强了白血病细胞中的FLT3信号转导。此外，药物抑制 FLT3-ITD 甲基化与 TKIs 联用可增加对 FLT3-ITD+ AML 细胞的清除。总之，这些结果表明，PRDM16 通过促使 FLT3-ITD 甲基化，促进了白血病细胞中的致癌 FLT3 信号转导。因此，PRDM16 可作为急性髓细胞白血病的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.