title: Inhibition of SRC corrects GM-CSF hypersensitivity that underlies juvenile myelomonocytic leukemia.
abstract: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm in children characterized by the overproduction of monocytic cells that infiltrate the spleen, lung, and liver. JMML remains a disease for which few curative therapies are available other than myeloablative hematopoietic stem cell transplant (HSCT); however, relapse remains a major cause of treatment failure and the long-term morbidities of HSCT for survivors are substantial. A hallmark feature of JMML is acquired hypersensitivity by clonal myeloid progenitor cells to granulocyte macrophage-colony stimulating factor (GM-CSF) via a largely unknown mechanism. Here, we identify c-Cbl (henceforth referred to as Cbl) as a GM-CSF receptor (GMR) adaptor protein that targets Src for ubiquitin-mediated destruction upon GM-CSF stimulation and show that a loss of negative regulation of Src is pivotal in the hyperactivation of GMR signaling in Cbl-mutated JMML cells. Notably, dasatinib, an U.S. Food and Drug Administration-approved multikinase inhibitor that also targets Src family, dramatically attenuated the spontaneous and GM-CSF-induced hypersensitive growth phenotype of mononuclear cells from peripheral blood and bone marrow collected from JMML patients harboring Cbl or other known JMML-associated mutations. These findings reveal Src kinase as a critical oncogenic driver underlying JMML.
authors: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: Severa
authors: S
authors: Bunda
authors: Michelle W
authors: MW
authors: Kang
authors: Stephanie S
authors: SS
authors: Sybingco
authors: Julie
authors: J
authors: Weng
authors: Helene
authors: H
authors: Favre
authors: Danielle H
authors: DH
authors: Shin
authors: Meredith S
authors: MS
authors: Irwin
authors: Mignon L
authors: ML
authors: Loh
authors: Michael
authors: M
authors: Ohh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053648:Cytokine Receptor Common beta Subunit; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050721:Proto-Oncogene Proteins c-cbl; D019061:src-Family Kinases; D000069439:Dasatinib