Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
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http://dx.doi.org/10.3324/haematol.2023.283776 | DOI Listing |
Pediatr Blood Cancer
December 2024
Pediatric Hematology-Oncology Department, University Children's Hospital of Basel, Basel, Switzerland.
Cancers (Basel)
December 2024
Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages. These clonal marrow disorders are extremely rare in pediatric patients. MPN is reported to occur 100 times more frequently in adults, and thus research is primarily focused on this patient group.
View Article and Find Full Text PDFMed Oncol
December 2024
Edmond H. Fischer Translational Medical Research Laboratory, Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm occurring in infants and young children. JMML has been shown to be resistant to all conventional cytotoxic chemotherapy drugs, and current curative therapies still rely on hematopoietic stem cell transplantation, which carries a high risk of relapse post-transplantation. This underscores the urgent need for novel treatment strategies.
View Article and Find Full Text PDFAm J Med Genet A
December 2024
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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