title: Critical signal transduction pathways in CLL.
abstract: Receptor tyrosine kinases (RTKs) are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play a critical role in signal transduction in both normal and malignant cells. Besides B cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL), multiple RTKs have been reported to be constitutively active in CLL B cells, resulting in enhanced survival and resistance to apoptosis of the leukemic cells induced by chemotherapeutic agents. In addition to increased plasma levels of various types of cytokines/growth factors in CLL, we and others have detected that CLL B cells spontaneously produce multiple cytokines in vitro which may constitute an autocrine loop of RTK activation on the leukemic B cells. Moreover, aberrant expression and activation of non-RTKs, for example, Src/Syk kinases, induce resistance of the leukemic B cells to therapy. Based on current available knowledge, we detailed the impact of aberrant activities of various RTKs/non-RTKs on CLL B cell survival and the potential of using these signaling components as future therapeutic targets in CLL therapy.
authors.affiliation: Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
mesh_terms: D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011947:Receptors, Antigen, B-Cell; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor