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Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study, we analyzed the expression of Bcl-2, Bax, and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine, and clinical outcome. Mcl-1 expression was significantly correlated with stage of disease (P < .001), lymphocyte doubling time (P = .01), V(H) gene mutation status (P < .001), CD38 expression (P < .001), and ZAP-70 expression (P = .003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P = .005 and P < .001, respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P < .001 and P < .001, respectively) and in stage A patients only (P = .002 and P = .001, respectively). Taken together, our data show that Mcl-1 is a key controller of in vitro drug resistance and is an important regulator of disease progression and outcome in CLL. It therefore represents a promising therapeutic target in this incurable condition. The close correlation between Mcl-1 expression and V(H) gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis.

Original publication

DOI

10.1182/blood-2008-05-157131

Type

Journal article

Journal

Blood

Publication Date

01/11/2008

Volume

112

Pages

3807 - 3817

Keywords

ADP-ribosyl Cyclase 1, Antineoplastic Agents, Biomarkers, Tumor, Cohort Studies, Drug Resistance, Neoplasm, Female, Humans, Immunoglobulin Heavy Chains, In Vitro Techniques, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Membrane Glycoproteins, Mutation, Myeloid Cell Leukemia Sequence 1 Protein, Prognosis, Proto-Oncogene Proteins c-bcl-2, Vidarabine, ZAP-70 Protein-Tyrosine Kinase