Pepper, Chris, Lin, Thet Thet, Pratt, Guy, Hewamana, Saman, Brennan, Paul , Hiller, Louise, Hills, R., Ward, Rachel, Starczynski, Jane, Austen, Belinda, Hooper, Laura, Stankovic, Tatjana and Fegan, Chris. (2008) Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood, Vol.112 (No.9). pp. 3807-3817. ISSN 0006-4971

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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 VH gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis. (Blood. 2008; 112:3807-3817)

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH301 Biology R Medicine > RB Pathology R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Lymphocytic leukemia -- Pathology, Apoptosis
Journal or Publication Title:	Blood
Publisher:	American Society of Hematology
ISSN:	0006-4971
Date:	1 November 2008
Volume:	Vol.112
Number:	No.9
Number of Pages:	11
Page Range:	pp. 3807-3817
Identification Number:	10.1182/blood-2008-05-157131
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Leukaemia Research UK (LRUK), Leukaemia Research Appeal for Wales, Welsh Bone Marrow Transplant Research Fund
URI:	http://wrap.warwick.ac.uk/id/eprint/29202

Data sourced from Thomson Reuters' Web of Knowledge

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