Kit-activating mutations in AML: lessons from PU.1-induced murine erythroleukemia.
In concert with its ligand, the stem cell factor (SCF), the receptor tyrosine kinase c-Kit acts as a key signaling molecule for a number of cell types, including hematopoietic stem cells, mast cells, melanocytes and germ cells. Gain-of-function mutations in c-Kit have been described in a number of human cancers, including testicular germinomas, acute myeloid leukemia and gastrointestinal stromal tumors. Yet their contribution to neoplastic growth is incompletely understood. Now Kosmider et al report the acquisition of Kit mutations in 86% of late-stage eryhtroleukemias in Spi-1/PU.1 transgenic mice. Without Kit mutations, these mice suffer from a benign disease whose hallmark is erythropoietin-dependent expansion of undifferentiated red blood cell precursors. Newly acquired Kit mutations affect codon 814 or 818, and ectopic expression of these mutants in nonmalignant pro-erythroblasts confers erythropoietin independence and tumorigenicity. Using tyrosine kinase inhibitors PP1, PP2, and imatinib mesylate (a.k.a. Gleevac), the authors demonstrate that Kit mutations are important for the autonomous expansion of malignant cells via the MEK/Erk1/2 and PI3K/Akt pathways. These findings validate the notion that one differentiation-blocking (e.g., PU.1 activation) and one proliferative (e.g., c-Kit mutations) event are required for the development of frank leukemia.
Cozma
Diana
D
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104-6051, USA.
Thomas-Tikhonenko
Andrei
A
D000818:Animals; D003062:Codon / Q000235:genetics; D004921:Erythropoietin / Q000502:physiology; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
D003062:Codon; D004921:Erythropoietin; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1