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

Content Provider	Springer Nature : BioMed Central
Author	Zhao, Yuming He, Chunxiao Zhang, Dengyang Guo, Yao Peng, Zhiyong Yu, Liuting Li, Na Chen, Chun Zhao, Zhizhuang Joe Chen, Yun
Abstract	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.
Related Links	https://ehoonline.biomedcentral.com/counter/pdf/10.1186/s40164-023-00379-1.pdf
Ending Page	6
Page Count	6
Starting Page	1
File Format	HTM / HTML
ISSN	21623619
DOI	10.1186/s40164-023-00379-1
Journal	Experimental Hematology & Oncology
Issue Number	1
Volume Number	12
Language	English
Publisher	BioMed Central
Publisher Date	2023-02-20
Access Restriction	Open
Subject Keyword	Hematology Oncology Cancer Research SHP2 Cell model JMML HCD-57
Content Type	Text
Resource Type	Correspondence
Subject	Hematology Oncology Cancer Research
Journal Impact Factor	9.4/2023
5-Year Journal Impact Factor	8.3/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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