Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Discov. 2022 Oct 5;12(10):2434-2453. doi: 10.1158/2159-8290.CD-21-1631.
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.
最近，在白血病中筛选 FLT3 和 ABL 激酶抑制剂的耐药调节剂的研究发现，LZTR1 是一种 Cullin-3 RING E3 泛素连接酶复合物的接头，负责 RAS GTP 酶的降解。与此同时，在克隆性造血条件下发现了通过异常剪接和突变导致的 LZTR1 表达失调。在这里，我们确定 LZTR1 的缺失，或逃避降解的 LZTR1 底物和 RAS GTP 酶 RIT1 的白血病相关突变，可驱动体内造血干细胞（HSC）的扩增和白血病。虽然 RIT1 的稳定足以驱动造血转化，但由 LZTR1 缺失介导的转化需要 MRAS。针对 RAS 的蛋白水解靶向嵌合体（PROTAC）或减少加载 GTP 的 RAS 可克服 LZTR1 缺失介导的对 FLT3 抑制剂的耐药性。这些数据揭示了非典型 RAS 蛋白的蛋白水解作为 HSC 自我更新的新型调节剂，定义了 RIT1 和 LZTR1 突变在白血病中的功能，并确定了克服由于 LZTR1 下调导致的耐药性的方法。
在这里，我们确定通过 LZTR1 下调或白血病相关突变稳定 RIT1 来削弱非典型 RAS GTP 酶 RIT1 和 MRAS 的蛋白水解作用，可增强 MAP 激酶的激活并驱动白血病发生。减少结合 GTP 的 KRAS 和 NRAS 的丰度可克服与 LZTR1 下调相关的对 FLT3 激酶抑制剂的耐药性。本文在本期的重点介绍文章中进行了强调，第 2221 页。
