Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers

• Published in: Blood 2008-11, Vol.112 (9), p.3807-3817
• Main Authors: Pepper, Chris, Lin, Thet Thet, Pratt, Guy, Hewamana, Saman, Brennan, Paul, Hiller, Louise, Hills, Robert, Ward, Rachel, Starczynski, Jane, Austen, Belinda, Hooper, Laura, Stankovic, Tatjana, Fegan, Chris
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase 1 - blood; Antineoplastic Agents - pharmacology; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Cohort Studies; Drug Resistance, Neoplasm; Female; Humans; Immunoglobulin Heavy Chains - genetics; In Vitro Techniques; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell - blood; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Male; Membrane Glycoproteins - blood; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Prognosis; Proto-Oncogene Proteins c-bcl-2 - blood; Proto-Oncogene Proteins c-bcl-2 - genetics; Vidarabine - analogs & derivatives; Vidarabine - pharmacology; ZAP-70 Protein-Tyrosine Kinase - blood
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-05-157131

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), VH 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 VH gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis.