LNK/<i>SH2B3</i> as a novel driver in juvenile myelomonocytic leukemia
Astrid Wintering,
Anna Hecht,
Julia Meyer,
Eric B. Wong,
Juwita Hübner,
Sydney Abelson,
Kira Feldman,
Vanessa E. Kennedy,
Cheryl A.C. Peretz,
Deborah L. French,
Jean Ann Maguire,
Chintan Jobaliya,
Marta Rojas Vasquez,
Sunil Desai,
Robin Dulman,
Eneida Nemecek,
Hilary Haines,
Mahmoud Hammad,
Alaa El Haddad,
Scott C. Kogan,
Zied Abdullaev,
Farid F. Chehab,
Sarah K. Tasian,
Catherine C. Smith,
Mignon L. Loh,
Elliot Stieglitz
Affiliations
Astrid Wintering
Department of Pediatrics, Benioff Children's Hospitals, University of California San Francisco, San Francisco, CA 94158
Anna Hecht
Department of Hematology/Oncology, Klinikum Rechts der Isar, Technische Universität München, München
Julia Meyer
Department of Pediatrics, Benioff Children's Hospitals, University of California San Francisco, San Francisco, CA 94158
Eric B. Wong
Department of Pediatrics, Benioff Children's Hospitals, University of California San Francisco, San Francisco, CA 94158
Juwita Hübner
Department of Pediatrics, Benioff Children's Hospitals, University of California San Francisco, San Francisco, CA 94158
Sydney Abelson
Department of Pediatrics, Benioff Children's Hospitals, University of California San Francisco, San Francisco, CA 94158
Kira Feldman
Department of Pediatrics, Benioff Children's Hospitals, University of California San Francisco, San Francisco, CA 94158
Vanessa E. Kennedy
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94158
Cheryl A.C. Peretz
Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158
Deborah L. French
Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104
Jean Ann Maguire
Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104
Chintan Jobaliya
Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104
Marta Rojas Vasquez
Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada
Sunil Desai
Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada
Robin Dulman
Pediatric Hematology and Oncology, Pediatric Specialists of Virginia, Fairfax, VA 22031
Eneida Nemecek
OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239
Hilary Haines
Children’s of Alabama, University of Alabama Hospital, Birmingham, AL 35233
Mahmoud Hammad
National Cancer Institute, Cairo University, Cairo, Egypt
Alaa El Haddad
National Cancer Institute, Cairo University, Cairo, Egypt
Scott C. Kogan
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94158
Zied Abdullaev
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814
Farid F. Chehab
Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143
Sarah K. Tasian
Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia; Philadelphia, PA 19104, USA; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 19104
Catherine C. Smith
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94158, USA; Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158
Mignon L. Loh
Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, and the Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, 98105
Elliot Stieglitz
Department of Pediatrics, Benioff Children's Hospitals, University of California San Francisco, San Francisco, CA 94158, USA; Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158
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 (HPCs) also demonstrated sensitivity of SH2B3- mutated HPCs 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.
