B cell receptor signaling in chronic lymphocytic leukemia.
B cell receptor (BCR) signaling plays an important pathogenic role in chronic lymphocytic leukemia (CLL) and B cell lymphomas, based on structural restrictions of the BCR, and BCR-dependent survival and growth of the malignant B cells. In CLL and lymphoma subtypes, ligand-independent ('tonic') and ligand-dependent BCR signaling have been characterized, which can involve mutations of BCR pathway components or be triggered by (auto)antigens present in the tissue microenvironment. In CLL, based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases [Bruton's tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K)δ], which will change treatment paradigms in CLL and other B cell malignancies. Here, we discuss the evolution of this field, from BCR-related prognostic markers, to mechanisms of BCR activation, and targeting of BCR-associated kinases, the emerging Achilles' heel in CLL pathogenesis.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address: jaburger@mdanderson.org.
Jan A
JA
Burger
Nicholas
N
Chiorazzi
D000818:Animals; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
D011947:Receptors, Antigen, B-Cell
B cell receptor; Bruton's tyrosine kinase; chronic lymphocytic leukemia; microenvironment; phosphoinositide 3-kinase δ; spleen tyrosine kinase