Granulocyte colony-stimulating factor and leukemogenesis.
The granulocyte colony-stimulating factor (G-CSF) plays an important role in normal granulopoiesis. Its functions are mediated by specific receptors on the surface of responsive cells and, upon ligand binding, several cytoplasmic tyrosine kinases are activated. The cytoplasmic region proximal to the membrane of the G-CSF receptor (G-CSF-R) transduces proliferative and survival signals, whereas the distal carboxy-terminal region transduces maturation signals and suppresses the receptor's proliferative signals. Mutations in the G-CSF-R gene resulting in truncation of the carboxy-terminal region have been detected in a subset of patients with severe congenital neutropenia who developed acute myelogenous leukemia (AML). In addition, the AML1-ETO fusion protein, expressed in leukemic cells harboring the t(8;21), disrupt the physiological function of transcription factors such as C/EBPalpha and C/EBPepsilon, which in turn deregulate G-CSF-R expression. The resulting high levels of G-CSF-R and G-CSF-dependent cell proliferation may be associated with pathogenesis of AML with t(8;21). Moreover, in vitro and in vivo studies demonstrated that G-CSF may act as a co-stimulus augmenting the response of PML-RARalpha acute promyelocytic leukemia cells to all-trans-retinoic acid treatment. Finally, in the PLZF-RARalpha acute promyelocytic leukemia transgenic model, G-CSF deficiency suppressed leukemia development. Altogether, these data suggest that the G-CSF signaling pathway may play a role in leukemogenesis.
de Figueiredo
Lorena Lobo
LL
Division of Hematology, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Campus USP, 14049-900, Ribeirão Preto, São Paulo, Brazil.
de Abreu e Lima
Rodrigo Siqueira
RS
Rego
Eduardo Magalhães
EM
D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000503:physiopathology*; D009503:Neutropenia / Q000503:physiopathology; D014178:Translocation, Genetic
D016179:Granulocyte Colony-Stimulating Factor