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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3538-3540.
Mcl-1: the 1 in CLLUNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER
Although Mcl-1 has been established as a survival and maintenance protein during in vitro incubations of primary CLL cells, in this issue of Blood, Pepper and colleagues further demonstrate the association of Mcl-1 with other prognostic factors and the role of this antiapoptotic protein in disease progression and outcome for patients with CLL.
Mcl-1 is essential during lymphoid development and maintenance of mature T and B lymphocytes1, and the expression level of antiapoptotic proteins in normal and malignant lymphocytes is in concordance with its role in survival.2 High levels of Mcl-1 and Bcl-2 mRNA and protein have been found in CLL, which are inversely correlated with in vitro response to chemotherapeutic agents or with the failure of CLL patients to respond to fludarabine therapy.3 Conversely, down-regulation of Mcl-1 protein expression by antisense oligonucleotides or through indirect Mcl-1 transcription and translation inhibitors results in cell death during in vitro culture or in vivo therapy. In addition, overexpression of Mcl-1 prolongs the survival of CLL cells exposed to a variety of apoptosis-inducing stimuli.2 These key pieces of evidence establish Mcl-1 as a critical survival factor for CLL. In this issue of Blood, Pepper et al use primary leukemia cells from a cohort of 185 patients with CLL to determine an association between antiapoptotic proteins and other prognostic parameters. To circumvent the qualitative nature of immunoblot analysis, flow cytometry was used to measure expression of antiapoptotic and proapoptotic proteins in a quantitative fashion. There is an expected heterogeneity among samples, yet the data beautifully demonstrate a relationship between Mcl-1 protein expression and other prognostic markers, such as stage of the disease, IgVH mutation status, ZAP-70 positivity, and CD38 expression. The study begs for analysis of other antiapoptotic and proapo-ptotic molecules, although they have included Bcl-2 and Bax. We also need to appreciate that quantitation of protein levels in 185 primary samples is a phenomenal effort. They also confirm association between these proteins and in vitro sensitivity to fludarabine, however, this was not a direct relationship; the correlation coefficients (r2 values) are not strong. Mcl-1 expression was also prognostic in overall survival of these patients and time to first treatment; the latter is under debate as there is not a consensus regarding the optimal time to treat CLL. Since the majority (70%) of the patients were of the Binet stage A, similar relationships were observed in this group also. Questions regarding a possible relationship between endogenous Mcl-1 levels and cytoreduction during therapy still remain unanswered. Nonetheless, the study provides new knowledge regarding the role of Mcl-1 in CLL patients, something that was previously assumed but now is substantiated by data and statistical analyses. So how can we take advantage of this knowledge? Since specific genetic targets are not defined in CLL, Mcl-1 seems to be an appropriate biomolecule to therapeutically manipulate. As shown in the figure, Mcl-1 protein production and maintenance are dependent on several pathways. At the apical level, the microenvironment provides factors that dramatically increase this protein in CLL cells.4 Hence, a strategy that interferes with interaction of microenvironment and CLL cells is a logical approach. Production of Mcl-1 through these signals is carried via increased transcription of the MCL-1 gene. Transcription and polyadenylation inhibition, albeit not selective, is an approach that works because of AU-rich elements in the transcript of Mcl-1, which leads to its rapid turnover.5 The N-terminal region of Mcl-1 protein contains 2 PEST domains that are rich in proline, glutamic acid, serine, and threonine residues, resulting in a short half-life of the protein5 and making translation inhibition and rapid degradation of endogenous Mcl-1 via proteasome pathway a viable option to reduce the protein level.6 Mcl-1 is also essential during early lymphoid development1 and is abundantly expressed in the germinal center B-cell compartment. Pim kinase and Akt-PI3–kinase pathways and down-stream of BLyS have been identified to maintain the Mcl-1 levels in B cells.7 The roles of these pathways and consequence of their perturbations need to be investigated in malignant lymphocytes. Similarly, work is needed on posttranslational modification leading to increased or decreased half-life of Mcl-1 protein. Finally, and probably most intriguingly, small molecule antagonists of Mcl-1 protein that bind to the BH3 domain releasing proapoptotic proteins provide a new avenue of research and therapeutics.2,8
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
