Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity

Abstract

Purpose: The antiapoptotic Bcl-2 family member protein Mcl-1is dynamically regulated in transformed B-cells, has a short mRNA and protein half-life, and is rapidly processed during apoptosis. Multiple therapies cause down-regulation of Mcl-1in chronic and acute lymphoid leukemia (CLL and ALL) cells. Mcl-1 has also been reported to mediate resistance to rituximab in CLL. We therefore investigated whether direct reduction of Mcl-1 was sufficient to induce apoptosis and increase sensitivity to rituximab. Experimental Design: We used Mcl-1^specific small interfering RNA in ALL cell lines and tumor cells from CLL patients to block transcription of Mcl-1. Results: We show that Mcl-1 down-regulation alone is sufficient to promote mitochondrial membrane depolarization and apoptosis in ALL and CLL cells. Given the importance of rituximab in B-cell malignancies, we next assessed the influence of Mcl-1 down-regulation on antibodymediated killing. Mcl-1 down-regulation by small interfering RNA increased sensitivity to rituximab-mediated killing both by direct apoptosis and complement-dependent cytotoxicity, but did not enhance antibody-dependent cellular cytotoxicity. Conclusions:These results show that Mcl-1is a relevant therapeutic target forALL and CLL, and its down-regulation has the potential to enhance the therapeutic effect of rituximab in CD20-bearing lymphoid cells.

Down-Regulation of Mcl-1 by Small Interference RNA Induces Apoptosis and Sensitizes HL-60 Leukemia Cells to Etoposide

“…Of note, we found that the inhibition of Mcl-1 using siRNA also resulted in significant apoptosis in the absence of etoposide, which is in contrast to the finding of others on solid tumors (Thallinger et al, 2003, Thallinger et al, 2004. However, this observation is similar to that found on other studies on hematological malignancies (Hussain et al, 2007;Quinn et al, 2011), illustrating the important biological role of Mcl-1 in leukemic cells. In addition, siMcl-1, in combination with etoposide dramatically enhanced apoptosis compared with siRNA alone or etoposide alone.…”

Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab

“…We recently showed, using Mcl-1-specific small interfering RNA, that Mcl-1 down-regulation alone is sufficient to promote mitochondrial membrane depolarization and apoptosis in CLL cells. 5 This Mcl-1 reduction also enhances CLL cell sensitivity to rituximab-mediated direct and complement-dependent cytotoxicity, but not antibodydependent cellular cytotoxicity. 5 Agents that target Mcl-1 protein expression in CLL cells, such as flavopiridol 19,20 and the novel agent silvestrol, 21 may therefore be of significant benefit in combination chemoimmunotherapy.…”

“…Mcl-1 modulation impacts response of CLL cells to various commonly used therapeutic agents, and loss of Mcl-1 is by itself sufficient to induce apoptosis in CLL cells. [5][6][7] Recent reports have also revealed a correlation between lower Mcl-1 protein 8 and mRNA levels 9 with known biologic prognostic markers and improved outcomes in patients with CLL.…”

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

“…42 Here, we provide evidence that MCL1 may be a redox-sensitive protein and its glutathionylation status could affect its stability. Because MCL1 has a critical role in prolonging the CLL cell survival, especially in a tumor-stroma context, 43,44 and is strongly associated with resistance to fludarabine, 28,29 rituximab, 45 chlorambucil, and prednisone, 46 the thiol-mediated abrogation of MCL1 by PEITC suggests a novel mechanism that may be exploited to overcome drug resistance by combining PEITC with these anti-CLL agents.…”