B-cell chronic lymphocytic leukemia: A bird of a different feather

Purpose: To review the recent major advances in the molecular and cell biol ogy of B-cell chronic lymphocytic leukemia (B-CLL), Methods: We analyzed the nature of malignant B-CLL B cells and their intera ctions with the microenvironment, Results: B-CLL is a malignancy of a mantle zone-based subpopulation of aner gic, self-reactive, activated CD5(+) B cells devoted to the production of p olyreactive natural autoantibodies. It is the quintessential example of a h uman malignancy that primarily involves defects in the induction of program med cell death. An abnormal karyotype is observed in about 50% of patients with B-CLL, patients with 13q14 abnormalities show heavy somatic mutation a nd have a benign disease. Trisomy 12 is associated with unmutated VH genes, atypical cellular morphology, and progressive disease, Extended cell survi val is further shielded by a kinetic refractoriness likely promoted by abno rmalities of the B-cell antigen receptor complex and favored by some cytoki nes that highlight a reciprocal dialog between malignant B and T cells. Bec ause the tumor cells act as the major accessory cells, the accumulating mal ignant B-cell population per se is a hurdle to the production of normal ant ibodies and leads to a progressive and severe hypogammaglobulinemia. Concei vably, in the presence of certain immunoglobulin genes and when the T-cell control becomes deficient, activated malignant B cells may become able to p resent self-antigens and drive residual normal B cells to produce polyclona l autoantibodies restricted to self-antigens expressed only by blood cells and cause autoimmune cytopenias, Conclusion: The distinctiveness of B-CLL B cells explains why B-CLL is diff erent from other B-cell tumors and accounts for the development of immune d eficiency and autoimmunity. J Clin Oncol 17:399-408, (C) 1999 by American Society of Clinical Oncology.