title: B-cell antigen receptor signaling in chronic lymphocytic leukemia: therapeutic targets and translational opportunities.
abstract: B-cell chronic lymphocytic leukemia (CLL) is characterized by clonally expanded and molecularly heterogeneous populations of B lymphocytes with impaired apoptotic mechanisms. This occurs as a result of multiple genetic and epigenetic abnormalities, including chromosomal aberrations and enhancer region hypomethylation, often impinging on intracellular signaling pathways that are essential to normal B-cell activation, proliferation, and survival. The B-cell antigen receptor (BCR) signaling is one such pathway usurped by malignant B cells, as exemplified by the early phase clinical success achieved by small-molecule agents targeting key players involved in the pathway. Such new targeted agents, including those that inhibit the function of Spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinases (PI3K), and B-cell lymphoma 2 (BCL-2), along with the current standard therapy comprising chemo-immunotherapies with or without B-cell depleting biologic agent rituximab (anti-CD20 monoclonal antibody), should expand the armamentarium for CLL therapy. We review the therapeutic agents currently in clinical development which target different effectors of the malignant BCR signaling, and discuss their overlapping and discriminating translational opportunities in the context of CLL treatment.
authors.affiliation: Principia Biopharma, South San Francisco, CA 94080, USA. ron.hill@principiabio.com
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hill
authors.forename: Yan
authors.initials: Y
authors.lastname: Lou
authors.forename: Seng-Lai
authors.initials: SL
authors.lastname: Tan
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase