title: Inhibiting B-cell receptor signaling pathways in chronic lymphocytic leukemia.
abstract: B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), or phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to "mobilization" of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.
authors: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA. jaburger@mdanderson.org
authors: Jan A
authors: JA
authors: Burger
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000631:Aminopyridines; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000503:physiopathology; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D052999:Quinazolinones / Q000627:therapeutic use; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D009025:Morpholines; D010078:Oxazines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D000225:Adenine; C523665:fostamatinib; C552946:idelalisib