Leukemogenic SHP2 mutations lead to erythropoietin independency of HCD-57 cells: a novel model for preclinical research of SHP2-mutant JMML

Experimental Hematology & Oncology

Correspondence

Zhizhuang Joe Zhao¹  Dengyang Zhang²  Chunxiao He²  Yao Guo²  Yuming Zhao²  Yun Chen²  Liuting Yu²  Na Li²  Chun Chen³  Zhiyong Peng⁴ 

[1] Department of Pathology, University of Oklahoma Health Sciences Center, 1100 N. Lindsay, 73104, Oklahoma City, OK, USA;Department of Pediatrics, Edmond H. Fischer Translational Medical Research Laboratory, Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China;Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China;Nanfang-Chunfu Children’s Institute of Hematology, Taixin Hospital, Dongguan, Guangdong, China;

关键词: SHP2;    Cell model;    JMML;    HCD-57;   

DOI  :  10.1186/s40164-023-00379-1

 received in 2022-10-29, accepted in 2023-02-05,  发布年份 2023

来源: Springer

【 摘 要 】

Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a rare but fatal hematopoietic malignancy without representative cell models, which are urgently needed to investigate the pathogenesis and to develop novel therapeutic strategies. In this study, we established stable cell lines with aberrant signaling resembling SHP2-mutant JMML through retroviral expression of SHP2-D61Y/E76K in HCD-57 cells, a murine erythroleukemia cell line that depends on erythropoietin (EPO) for survival. SHP2-D61Y/E76K drives the survival and proliferation of HCD-57 cells in the absence of EPO, but not in Ba/F3 cells in the absence of IL-3. Transformed HCD-57 cells showed activated MAPK signaling that is consistent with SHP2-mutant JMML. Transformed HCD-57 cells were sensitive to dasatinib and trametinib, two targeted drugs previously reported to inhibit SHP2-mutant JMML cells. Furthermore, we injected mutant SHP2-transformed HCD-57 cells into immune-deficient mice intravenously and found that these cells rapidly proliferated in the spleen and bone marrow, providing an excellent model for in vivo testing of drugs targeting the aberrant signaling of mutant SHP2. In conclusion, we established the novel cell lines HCD-57/SHP2-E76K and -D61Y that depended on signaling of mutant SHP2 for survival, thus resembling SHP2-mutant JMML. Our model is a valuable tool to investigate the pathogenic mechanisms of mutant SHP2 and targeted drugs for SHP2-mutant JMML.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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