title: Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers.
abstract: 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.
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom. peppercj@cf.ac.uk
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.forename: Thet Thet
authors.initials: TT
authors.lastname: Lin
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Saman
authors.initials: S
authors.lastname: Hewamana
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.forename: Rachel
authors.initials: R
authors.lastname: Ward
authors.forename: Jane
authors.initials: J
authors.lastname: Starczynski
authors.forename: Belinda
authors.initials: B
authors.lastname: Austen
authors.forename: Laura
authors.initials: L
authors.lastname: Hooper
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000097:blood; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D066298:In Vitro Techniques; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood* / Q000235:genetics; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D014740:Vidarabine; C024352:fludarabine