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

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          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.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s40164-023-00379-1.

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          Most cited references12

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          Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

          We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.
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            RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

            Oncogenic alterations in the RAS-RAF-MEK-ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the PTPN11/SHP2 phosphatase with RMC-4550, a small molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (e.g. KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.
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              The role of Shp2 (PTPN11) in cancer.

              Tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs), regulates numerous cellular processes. Altered expression and/or mutations in PTKs are linked to many forms of cancer, yet until recently little was known about the roles of PTPs in normal cells or in cancer. Earlier work established that a member of the PTP superfamily, PTEN, is an important tumor suppressor gene. We now know that at least one other PTP, the SH2 domain-containing phosphatase Shp2, is a bona fide oncogene that is mutated in several types of leukemia and hyperactivated by other mechanisms in some solid tumors. Understanding how Shp2 and other PTPs contribute to oncogenesis should provide new insights into pathogenesis and might suggest new targets for anti-neoplastic drugs.
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                Author and article information

                Contributors
                chenchun@mail.sysu.edu.cn
                joe-zhao@ouhsc.edu
                cheny653@mail.sysu.edu.cn
                Journal
                Exp Hematol Oncol
                Exp Hematol Oncol
                Experimental Hematology & Oncology
                BioMed Central (London )
                2162-3619
                20 February 2023
                20 February 2023
                2023
                : 12
                : 20
                Affiliations
                [1 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Pediatrics, Edmond H. Fischer Translational Medical Research Laboratory, Scientific Research Center, The Seventh Affiliated Hospital, , Sun Yat-Sen University, ; Shenzhen, 518107 Guangdong China
                [2 ]Nanfang-Chunfu Children’s Institute of Hematology, Taixin Hospital, Dongguan, Guangdong China
                [3 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Pediatrics, The Seventh Affiliated Hospital, , Sun Yat-Sen University, ; Shenzhen, 518107 Guangdong China
                [4 ]GRID grid.266902.9, ISNI 0000 0001 2179 3618, Department of Pathology, , University of Oklahoma Health Sciences Center, ; 1100 N. Lindsay, Oklahoma City, OK 73104 USA
                Article
                379
                10.1186/s40164-023-00379-1
                9940371
                b7812efb-776d-4574-9835-8f5c80b42b15
                © The Author(s) 2023

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 29 October 2022
                : 5 February 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82202579
                Award ID: 82000150
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100012151, Sanming Project of Medicine in Shenzhen;
                Award ID: SZSM202011004
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100011516, Guangdong Provincial Key Laboratory of Reproductive Medicine;
                Award ID: 2021B1212040006
                Award Recipient :
                Funded by: Guangdong Basic and Applied Basic Research Foundation
                Award ID: 2019A1515110121
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100010877, Science, Technology and Innovation Commission of Shenzhen Municipality;
                Award ID: JCYJ20190814164601648
                Award ID: JCYJ20210324123003009
                Award ID: JCYJ20210324123210028
                Award ID: JCYJ20220530144814032
                Award Recipient :
                Categories
                Correspondence
                Custom metadata
                © The Author(s) 2023

                Oncology & Radiotherapy
                shp2,cell model,jmml,hcd-57
                Oncology & Radiotherapy
                shp2, cell model, jmml, hcd-57

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