Zhao Yuming, Chang Zhiguang, Hu Bingbing, Zhang Qi, Zhang Dengyang, He Chunxiao, Guo Yao, Peng Zhiyong, Chen Chun, Chen Yun
Edmond H. Fischer Translational Medical Research Laboratory, Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
Reproductive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
Front Oncol. 2023 Jan 30;13:1090542. doi: 10.3389/fonc.2023.1090542. eCollection 2023.
Gain-of-function mutations of SHP2, especially D61Y and E76K, lead to the development of neoplasms in hematopoietic cells. Previously, we found that SHP2-D61Y and -E76K confer HCD-57 cells cytokine-independent survival and proliferation activation of MAPK pathway. Metabolic reprogramming is likely to be involved in leukemogenesis led by mutant SHP2. However, detailed pathways or key genes of altered metabolisms are unknown in leukemia cells expressing mutant SHP2. In this study, we performed transcriptome analysis to identify dysregulated metabolic pathways and key genes using HCD-57 transformed by mutant SHP2. A total of 2443 and 2273 significant differentially expressed genes (DEGs) were identified in HCD-57 expressing SHP2-D61Y and -E76K compared with parental cells as the control, respectively. Gene ontology (GO) and Reactome enrichment analysis showed that a large proportion of DEGs were involved in the metabolism process. Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis showed that DEGs were the mostly enriched in glutathione metabolism and biosynthesis of amino acids in metabolic pathways. Gene Set Enrichment Analysis (GSEA) revealed that the expression of mutant SHP2 led to a significant activation of biosynthesis of amino acids pathway in HCD-57 expressing mutant SHP2 compared with the control. Particularly, we found that , , , and involved in the biosynthesis of asparagine, serine, and glycine were remarkably up-regulated. Together, these transcriptome profiling data provided new insights into the metabolic mechanisms underlying mutant SHP2-driven leukemogenesis.
SHP2的功能获得性突变，尤其是D61Y和E76K，会导致造血细胞发生肿瘤。此前，我们发现SHP2-D61Y和-E76K赋予HCD-57细胞不依赖细胞因子的存活和增殖能力，并激活MAPK途径。代谢重编程可能参与了由突变型SHP2引发的白血病发生过程。然而，在表达突变型SHP2的白血病细胞中，代谢改变的详细途径或关键基因尚不清楚。在本研究中，我们使用由突变型SHP2转化的HCD-57细胞进行转录组分析，以鉴定失调的代谢途径和关键基因。与作为对照的亲代细胞相比，在表达SHP2-D61Y和-E76K的HCD-57细胞中分别鉴定出2443个和2273个显著差异表达基因（DEG）。基因本体（GO）和Reactome富集分析表明，大部分DEG参与了代谢过程。京都基因与基因组百科全书（KEGG）途径富集分析表明，DEG在代谢途径中主要富集于谷胱甘肽代谢和氨基酸生物合成。基因集富集分析（GSEA）显示，与对照相比，突变型SHP2的表达导致表达突变型SHP2的HCD-57细胞中氨基酸生物合成途径显著激活。特别地，我们发现参与天冬酰胺、丝氨酸和甘氨酸生物合成的 、 、 和 显著上调。总之，这些转录组分析数据为突变型SHP2驱动的白血病发生的代谢机制提供了新的见解。
