Abstract
The pathogenesis of juvenile myelomonocytic leukemia (JMML) has been speculated to arise from dysregulation of the Ras signal transduction pathway. It is a hallmark for JMML that leukemic cells demonstrate selective hypersensitivity in vitro to granulocyte macrophage colony-stimulating factor (GM-CSF). Until now, genetic abnormalities in three genes (protein-tyrosine phosphatase, non-receptor type 11 [PTPN11]), RAS, and neurofibromatosis type 1 [NF1]), all of which are positioned in the GM-CSF/Ras signal transduction pathway, account for up to 75% of patients with JMML. Approximately 20 to 30% of patients with JMML have activating RAS mutations, and 12 to 15% of patients with JMML have inactivating NF1 mutations. Mutations in PTPN11 were demonstrated to account for approximately 50% of patients with Noonan syndrome. Interestingly, approximately 30 to 40% of patients with JMML without clinical manifestations of Noonan syndrome have PTPN11 mutations. These mutations are mutually exclusive and functionally equivalent in their involvement in JMML pathogenesis. In this article, we describe the recent advances in the pathogenesis of JMML, especially focusing on the role of PTPN11 mutations.
