**2.3. Mcl-1 and CLL**

Mcl-1 is one of the Bcl-2-related survival proteins but is somewhat structurally distinct and probably lacks a "classical" BH4 domain. It was first discovered in differentiating myeloid cells where Mcl-1 is thought to play a transient role in promoting cell survival, but it has been expressed in various malignant cells, like CLL. Overexpression of Mcl-1 in CLL cells associated with a failure to achieve complete remission following cytotoxic therapy [42].

Mcl-1 protein has a rapid turnover, and it has a short half-life (a few hours). Mcl-1 has a critical role in regulating apoptosis in response to rapidly changing environmental cues. During apoptosis, Mcl-1 is a very efficient substrate for caspases [43–46]. While Mcl-1 is an antiapoptotic protein, its cleavage by caspases converts it into a cell-death-promoting molecule [43]. Therefore, Mcl-1

**Figure 6.** Regulation of apoptosis by the Bcl-2 family [26].

can act as a molecular bodyguard or assassin during apoptosis [47]. Saxena et al. showed that Mcl-1 can play an important role in CLL, by insertion of small sequences in its promoter [47]. They showed the presence of specific insertions in 29% patients with CLL and while in none of the controls. They found that these insertions were correlated with rapid disease progression, with a poor response to chemotherapy and shorter disease-specific survival. By founding of insertions in CD38-negative patients, they suggest that a poor prognostic marker [47] can be present.

Finally, since specific genetic targets are not defined in CLL, Mcl-1 seems to be an appropriate biomolecule to therapeutically manipulate. 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 [48]. Hence, a strategy that interferes with the 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 [49]. The N-terminal region of Mcl-1 protein contains 2PEST domains that are rich in proline, glutamic acid, serine, and threonine residues, resulting in a short half-life of the protein [49] and making translation inhibition and rapid degradation of endogenous Mcl-1 via proteasome pathway a viable option to reduce the protein level [50]. Mcl-1 is also essential during early lymphoid development [51] and is abundantly expressed in the germinal center B-cell compartment. Pim kinase and Akt-PI3-kinase pathways and downstream of BLyS have been identified to maintain the Mcl-1 levels in B-cells [52]. 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.
