Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation.
Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation.
复制标题
DOI：
10.1158/2159-8290.cd-21-1631
复制
发表时间：
2022-10-05
期刊：
影响因子：
28.2
通讯作者：
中科院分区：
文献类型：
--
作者：
LZTR 1（Cullin-3 RING E3泛素连接酶衔接子）的功能丧失改变以及通过RIT 1突变受损的泛素介导的RAS蛋白降解驱动克隆造血转化最近，在白血病中筛选对FLT 3和ABL激酶抑制剂耐药的介质导致发现LZTR 1作为负责RAS GTP酶降解的Cullin-3 RING E3泛素连接酶复合物的衔接子。与此同时，在克隆造血条件下，通过异常剪接和突变确定了LZTR 1表达失调。在这里，我们确定LZTR 1或LZTR 1底物中的白血病相关突变体和逃避降解的RAS GTCRIT 1的丢失，驱动体内造血干细胞（HSC）扩增和白血病。虽然RIT 1稳定足以驱动造血转化，但由LZTR 1缺失介导的转化需要MRAS。针对RAS的蛋白水解靶向嵌合体（PROTAC）或负载GTP的RAS的减少克服了LZTR 1损失介导的对FLT 3抑制剂的抗性。这些数据揭示了非经典RAS蛋白的蛋白水解作为HSC自我更新的新型调节剂，定义了RIT 1和LZTR 1突变在白血病中的功能，并确定了克服LZTR 1下调引起的耐药性的方法。在这里，我们确定，通过LZTR 1下调或白血病相关突变稳定RIT 1，非经典RAS GTP酶RIT 1和MRAS的蛋白水解受损增强MAP激酶激活和驱动白血病发生。减少GTP结合的KRAS和NRAS的丰度克服了对与白血病中LZTR 1下调相关的FLT 3激酶抑制剂的抗性。 这篇文章在本期专题中突出显示，第2221页
Loss-of-function alterations in LZTR1, a Cullin-3 RING E3 ubiquitin ligase adapter, and impaired ubiquitin-mediated degradation of RAS proteins via mutations in RIT1 drive clonal hematopoietic transformation. Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation. Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia. This article is highlighted in the In This Issue feature, p. 2221