HMGCS1通过MAPK通路调控白血病细胞的增殖及其机制

Leukemia is a common hematological malignancy. The major treatments, including chemotherapy and bone marrow transplantation, still have obvious drawbacks. Discovery of novel targets are needed to improve the therapeutic effects. Cancer cells utilize unique metabolic alteration to satisfy the needs of fast proliferation. Many metabolic genes and metabolites involved in mevalonate pathway (MVA pathway) are pivotal for cancer cells. HMGCS1 is an upper-stream gene in MVA pathway, which has not been studied in leukemia cells. Previously, the applicant had demonstrated that HMGCS1 can promote cell proliferation in BRAFV600E mutated cancer cells both in vitro and in vivo. Intriguingly, we discovered that HMGCS1 expression was obviously elevated in relapsed leukemia patients when compared to remissive patients, indicating HMGCS1 may play an important role. Therefore, this project aims to figure out the function of HMGCS1 in leukemia cells and the underlying mechanisms. Combining data from our preliminary research and literature, we hypothesize that HMGCS1 regulates MAPK signal pathway activity through affecting Ras isoprenytion, and therefore promotes leukemia cell growth. In this project, we will make use of both molecular tools (eg.CRISPR-Cas9) and cellular techniques to confirm previous data in multiple cell lines, CDX/PDX mouse models and clinical leukemia samples. Furthermore, we will study the function of Hymeglusin, the specific HMGCS1 inhibitor, with the prospect of its translation to clinic.

白血病是血液系统常见的恶性肿瘤，目前主要的治疗方法，如化疗及移植，尚存在明显不足，需寻找新的治疗靶点提高疗效。肿瘤利用独特的代谢改变以满足快速增长的需要。例如甲羟戊酸代谢通路中的多种基因、中间产物在肿瘤中均有重要功能。HMGCS1是该通路的上游基因，在白血病中的作用尚无研究。申请人前期在体内外水平证实了HMGCS1在BRAFV600E肿瘤中有促细胞生长的作用。前期研究发现复发组白血病患者的HMGCS1mRNA水平明显高于缓解组，表明HMGCS1在白血病中有重要作用。综合前期研究及文献资料，我们提出假设：HMGCS1通过影响Ras的异戊二烯化，激活MAPK信号通路，从而促进白血病细胞的增殖。本课题将利用CRISPR-Cas9等技术在多株细胞中验证前期结果、探讨其具体机制，并且在CDX、PDX动物模型及临床标本中加以验证；并研究其抑制剂Hymeglusin的作用，有望使其转化应用于临床。

急性白血病通过特异的代谢改变以满足快速增长的需要，代谢弱点成为潜在的治疗靶点。通过对比正常人及AML患者的血脂水平，发现AML存在异常的胆固醇代谢。TCGA大数据库及RNA-Seq测序分析表明MVA代谢通路中的多个基因在AML中表达增高，且该通路的上游基因HMGCS1的水平与AML的生存时间呈负相关。为进一步证实HMGCS1在AML中的作用，我们利用CRISP-CAS9技术调控HMGCS1表达水平建立过表达及敲除细胞株，同时使用其抑制剂hymeglusin处理AML细胞。结果表明，HMGCS1通过代谢中间产物FPP及GGPP激活MAPK信号通路，从而促进白血病细胞的增殖。此外，HMGCS1通过影响BCL2的表达抑制细胞凋亡。而其特异性抑制剂Hymeglusin 能显著抑制白血病细胞增殖、促进细胞凋亡，且对正常的人外周血单个核细胞无明显毒性。本项目的成果证实了hymeglusin的潜在抗白血病作用，有望使其转化应用于临床。