突变型FMS样酪氨酸激酶-3的选择性降解需要热休克蛋白的BIM依赖性消耗

IF 12.8 1区 医学 Q1 HEMATOLOGY
Melisa Halilovic, Mohamed Abdelsalam, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Matthias Schmidt, Walburgis Brenner, Sara Najafi, Ina Oehme, Christoph Hieber, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H. Krämer
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引用次数: 0

摘要

FMS样酪氨酸激酶-3(FLT3-ITD)的内部串联重复是急性髓性白血病(AML)中常见的突变。蛋白水解靶向嵌合体(PROTACs)能诱导蛋白酶体降解突变的FLT3,是一种创新的药理学方法。除了泛素-蛋白酶体系统外,控制靶向蛋白酶解的分子机制尚未明确,而PROTACs是目前已知的唯一一种FLT3降解剂。我们报告说,基于von-Hippel-Lindau泛素连接酶的FLT3 PROTAC MA49(美洛替尼-49)和FLT3疏水标签分子MA50(哈洛替尼-50)可减少内质网相关的致癌FLT3-ITD,但不影响FLT3。纳摩尔剂量的 MA49 和 MA50 能诱导带有 FLT3-ITD 的人类白血病细胞系和原发性急性髓细胞白血病细胞凋亡(p < 0.05-0.0001),但不能诱导原发性造血干细胞和分化的免疫细胞、FLT3 野生型细胞、视网膜细胞和 c-KIT 依赖性细胞凋亡。MA49 对 FLT3-ITD 阳性白血病细胞的体内活性已在 Danio rerio 模型中得到验证。降解剂诱导的 FLT3-ITD 损失涉及促凋亡的 BH3 唯一蛋白 BIM 和先前未确定的降解剂诱导的蛋白质折叠伴侣的消耗。HSP90 和 HSP110 的表达水平与急性髓细胞性白血病患者存活率的降低相关(p < 0.1),HSP90、HSP110 和 BIM 与原发性急性髓细胞性白血病细胞中 FLT3 的表达相关(p < 0.01)。HSP90抑制了降解剂诱导的FLT3-ITD消除,从而建立了一个机理明确的反馈回路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins

Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins

Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins
Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (p < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a Danio rerio model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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