Medical Biology - Research Publications
Permanent URI for this collection
Search Results
1 - 3 of 3
-
ItemNo Preview AvailableBCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines(AMER SOC HEMATOLOGY, 2020-01-28)Dysregulated expression of BCL-2 family proteins allows cancer cells to escape apoptosis. To counter this, BH3-mimetic drugs that target and inhibit select BCL-2 prosurvival proteins to induce apoptosis have been developed for cancer therapy. Venetoclax, which targets BCL-2, has been effective as therapy for patients with chronic lymphocytic leukemia, and MCL-1-targeting BH3-mimetic drugs have been extensively evaluated in preclinical studies for a range of blood cancers. Recently, BCL-W, a relatively understudied prosurvival member of the BCL-2 protein family, has been reported to be abnormally upregulated in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma patient samples. Therefore, to determine if BCL-W would be a promising therapeutic target for B-cell lymphomas, we have examined the role of BCL-W in the sustained growth of human BL- and DLBCL-derived cell lines. We found that CRISPR/CAS9-mediated loss or short hairpin RNA-mediated knockdown of BCL-W expression in selected BL and DLBCL cell lines did not lead to spontaneous apoptosis and had no effect on their sensitivity to a range of BH3-mimetic drugs targeting other BCL-2 prosurvival proteins. Our results suggest that BCL-W is not universally required for the sustained growth and survival of human BL and DLBCL cell lines. Thus, targeting BCL-W in this subset of B-cell lymphomas may not be of broad therapeutic benefit.
-
ItemNo Preview AvailableMCL-1 is essential for survival but dispensable for metabolic fitness of FOXP3+regulatory T cells(SPRINGERNATURE, 2020-12)FOXP3+ regulatory T (Treg) cells are essential for maintaining immunological tolerance. Given their importance in immune-related diseases, cancer and obesity, there is increasing interest in targeting the Treg cell compartment therapeutically. New pharmacological inhibitors that specifically target the prosurvival protein MCL-1 may provide this opportunity, as Treg cells are particularly reliant upon this protein. However, there are two distinct isoforms of MCL-1; one located at the outer mitochondrial membrane (OMM) that is required to antagonize apoptosis, and another at the inner mitochondrial membrane (IMM) that is reported to maintain IMM structure and metabolism via ATP production during oxidative phosphorylation. We set out to elucidate the relative importance of these distinct biological functions of MCL-1 in Treg cells to assess whether MCL-1 inhibition might impact upon the metabolism of cells able to resist apoptosis. Conditional deletion of Mcl1 in FOXP3+ Treg cells resulted in a lethal multiorgan autoimmunity due to the depletion of the Treg cell compartment. This striking phenotype was completely rescued by concomitant deletion of the apoptotic effector proteins BAK and BAX, indicating that apoptosis plays a pivotal role in the homeostasis of Treg cells. Notably, MCL-1-deficient Treg cells rescued from apoptosis displayed normal metabolic capacity. Moreover, pharmacological inhibition of MCL-1 in Treg cells resistant to apoptosis did not perturb their metabolic function. We conclude that Treg cells require MCL-1 only to antagonize apoptosis and not for metabolism. Therefore, MCL-1 inhibition could be used to manipulate Treg cell survival for clinical benefit without affecting the metabolic fitness of cells resisting apoptosis.
-
ItemToward Targeting Antiapoptotic MCL-1 for Cancer Therapy(ANNUAL REVIEWS, 2020)Apoptosis is critical for embryonic development, tissue homeostasis, and the removal of infected or otherwise dangerous cells. It is controlled by three subgroups of the BCL-2 protein family—the BH3-only proteins that initiate cell death; the effectors of cell killing, BAX and BAK; and the antiapoptotic guardians, including MCL-1 and BCL-2. Defects in apoptosis can promote tumorigenesis and render malignant cells refractory to anticancer therapeutics. Activation of cell death by inhibiting antiapoptotic BCL-2 family members has emerged as an attractive strategy for cancer therapy, with the BCL-2 inhibitor venetoclax leading the way. Large-scale cancer genome analyses have revealed frequent amplification of the locus encoding antiapoptotic MCL-1 in human cancers, and functional studies have shown that MCL-1 is essential for the sustained survival and expansion of many types of tumor cells. Structural analysis and medicinal chemistry have led to the development of three distinct small-molecule inhibitors of MCL-1 that are currently undergoing clinical testing.