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

Chris Pepper, Thet Thet Lin, Guy Pratt, Saman Hewamana, Paul Brennan, Louise Hiller, Robert Hills, Rachel Ward, Jane Starczynski, Belinda Austen, Laura Hooper, Tatjana Stankovic, Chris Fegan

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175 Citations (Scopus)

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), 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.
Original languageEnglish
Pages (from-to)3807-3817
Number of pages11
JournalBlood
Volume112
Issue number9
DOIs
Publication statusPublished - 1 Nov 2008
Externally publishedYes

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