Department of Pediatrics, University of California-San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
Blood. 2012 Jan 26;119(4):1032-5. doi: 10.1182/blood-2011-06-358960. Epub 2011 Dec 5.
The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-Ras(G12D) formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations.
翻译后修饰的棕榈酰化/去棕榈酰化循环是选择性抑制伴有体细胞NRAS突变的血液系统癌症生长的一个潜在治疗靶点。为了在单细胞水平研究这个问题，我们构建了鼠干细胞病毒载体并检测了髓系祖细胞的生长情况。表达致癌性N-Ras(G12D)的细胞形成了不依赖细胞因子的集落，并且对GM-CSF高度敏感，而N-Ras高变区内的突变导致N-Ras定位错误并减弱了异常祖细胞的生长。将转导的造血细胞以及来自Nras和Kras突变小鼠的骨髓暴露于酰基蛋白硫酯酶抑制剂棕榈抑素B，对蛋白质定位和集落生长有类似影响。重要的是，棕榈抑素B介导的抑制作用对Nras突变细胞具有选择性，并且我们将这种活性定位到高变区。这些数据支持去棕榈酰化抑制剂作为一类针对伴有NRAS突变的血液系统恶性肿瘤的新型合理疗法进行临床开发。
