scholarly journals The multiple mechanisms of MCL1 in the regulation of cell fate

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hayley Widden ◽  
William J. Placzek
Keyword(s):  
Cell Fate ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Calcium Handling ◽  
Mitochondrial Quality Control ◽  
Disease States ◽  
Promising Target ◽  
Damage Response ◽  
Homeostasis Regulation

AbstractMCL1 (myeloid cell leukemia-1) is a widely recognized pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) family and a promising target for cancer therapy. While the role MCL1 plays in apoptosis is well defined, its participation in emerging non-apoptotic signaling pathways is only beginning to be appreciated. Here, we synthesize studies characterizing MCL1s influence on cell proliferation, DNA damage response, autophagy, calcium handling, and mitochondrial quality control to highlight the broader scope that MCL1 plays in cellular homeostasis regulation. Throughout this review, we discuss which pathways are likely to be impacted by emerging MCL1 inhibitors, as well as highlight non-cancerous disease states that could deploy Bcl-2 homology 3 (BH3)-mimetics in the future.

scholarly journals Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Kamil Bojarczuk ◽  
Kirsty Wienand ◽  
Jeremy A. Ryan ◽  
Linfeng Chen ◽  
Mariana Villalobos-Ortiz ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Xenograft Model ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Synergistic Activity ◽  
Genetic Bases

Abstract Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1–dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2–mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

2020 ◽  
Author(s):  
Melissa A. Fischer ◽  
Yuanbin Song ◽  
Rana Gbyli ◽  
Maria P. Arrate ◽  
Matthew T. Villaume ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Bcl2 Family ◽  
Apoptotic Protein ◽  
Clinical Complexity ◽  
Therapeutic Opportunity ◽  
Dual Inhibition

AbstractTreatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and clinical complexity. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma-2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML). BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. Here, we determined the in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with increasing blast counts, all MDS subtypes responded to the MCL1 inhibitor, S63845. Treatment with combined VEN+S63845 was synergistic in all MDS subtypes and reduced MDS engraftment in MISTRG6 mice supporting the pursuit of clinical trials with combined BCL2+MCL1 inhibition in MDS.

scholarly journals The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

2019 ◽  
Vol 120 (12) ◽  
pp. 1137-1146 ◽  
Author(s):  
Anke Maes ◽  
Ken Maes ◽  
Hendrik De Raeve ◽  
Eva De Smedt ◽  
Philip Vlummens ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Anaphase Promoting Complex ◽  
Large B Cell Lymphoma ◽  
Promising Target ◽  
Mantle Cell ◽  
Large B Cell

scholarly journals Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Bojie Yang ◽  
Quansheng Liu ◽  
Yuanhong Bi
Keyword(s):  
Endoplasmic Reticulum ◽  
B Cell ◽  
Cell Fate ◽  
Cell Lymphoma ◽  
Feedback Regulation ◽  
B Cell Lymphoma ◽  
Regulatory Mechanisms ◽  
Time Duration ◽  
Cell Fate Decisions ◽  
Different Levels

Abstract Background Autophagy and apoptosis are two important physiological processes that determine cell survival or death in response to different stress signals. The regulatory mechanisms of these two processes share B-cell lymphoma-2 family proteins and AMBRA1, which are present in both the endoplasmic reticulum and mitochondria. B-cell lymphoma-2 family proteins sense different stresses and interact with AMBRA1 to regulate autophagy and apoptosis, which are respectively mediated by Beclin1 and Caspases. Therefore, we investigated how different levels of stress on B-cell lymphoma-2 family proteins that bind to AMBRA1 in the endoplasmic reticulum and mitochondria regulate the switch from autophagy to apoptosis. Methods In this paper, we considered the responses of B-cell lymphoma-2 family proteins, which bind to AMBRA1 in both the endoplasmic reticulum and mitochondria, to two different levels of stress in a model originally proposed by Kapuy et al. We investigated how these two stress levels affect the transition from autophagy to apoptosis and their effects on apoptosis activation over time. Additionally, we analyzed how the feedback regulation in this model affects the bifurcation diagrams of two levels of stress and cell fate decisions between autophagy and apoptosis. Results Autophagy is activated for minor stress in mitochondria regardless of endoplasmic reticulum stress, while apoptosis is activated for only significant stress in mitochondria. Apoptosis is only sensitive to mitochondria stress. The time duration before apoptosis activation is longer in the presence of high AMBRA1 levels with high endoplasmic reticulum and mitochondria stress. AMBRA1 can compete with B-cell lymphoma-2 family proteins to bind and activate Beclin1 and thus promote the autophagy process for a long time before apoptosis. Furthermore, apoptosis is prone to occur with increasing activation of Caspases, inactivation of Beclin1-A and the Michaelis constant of Caspases. Conclusion A novel mathematical model has been developed to understand the complex regulatory mechanisms of autophagy and apoptosis. Our model may be applied to further autophagy-apoptosis dynamic modeling experiments and simulations.

scholarly journals tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma

2013 ◽  
Vol 110 (4) ◽  
pp. 1404-1409 ◽  
Author(s):  
Roy L. Maute ◽  
Christof Schneider ◽  
Pavel Sumazin ◽  
Antony Holmes ◽  
Andrea Califano ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Cell ◽  
Dna Damage Response ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Damage Response

scholarly journals Overexpression of B‐cell lymphoma 6 alters gene expression profile in a myeloma cell line and is associated with decreased DNA damage response

2017 ◽  
Vol 108 (8) ◽  
pp. 1556-1564 ◽  
Author(s):  
Kenichi Tahara ◽  
Makiko Takizawa ◽  
Arito Yamane ◽  
Yohei Osaki ◽  
Takuma Ishizaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
B Cell ◽  
Cell Line ◽  
Dna Damage Response ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Myeloma Cell ◽  
Myeloma Cell Line ◽  
Damage Response

Recent Advances in Chemotherapeutic Implications of Deguelin, A Plant Derived Retinoid

2020 ◽  
Vol 10 ◽  
Author(s):  
Manzoor A Mir ◽  
Umar Mehraj ◽  
Bashir A Sheikh
Keyword(s):  
B Cell ◽  
Therapeutic Agent ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
Cancer Chemoprevention ◽  
B Cell Lymphoma ◽  
Signalling Pathway ◽  
Therapeutic Effects ◽  
Underlying Mechanisms ◽  
And Migration

Deguelin, a plant retinoid has emerged to be a promising therapeutic agent in the treatment of different cancers. Recent studies demonstrate that deguelin has potential as an angiogenesis antagonist in malignant and endothelial cells by specifically targeting HGF-c-Met and VEGF-VEGFR pathways. It is reported to have profound therapeutic effects in pancreatic cancer by inactivation of the hedgehog (Hh) signalling pathway and suppresses the expression of matrix metalloproteinases such as MMP-2 and MMP-9. The basic underlying mechanisms for deguelin mediated anti-NSCLC effect were uncovered through its induction of elevated intracellular reactive oxygen species (ROS) levels and suppression of the PI3K /Akt-HK2 signalling pathway. Deguelin induces cell apoptosis by targeting various pathways most notably regulating expression of galectin-1 and binding directly to anti-apoptotic Bcl-2 (B-cell lymphoma 2), Bcl-xl (B-cell lymphoma-extralarge) and Mcl-1 (Myeloid Cell Leukemia Sequence 1) in the hydrophobic grooves thereby liberating BAD and BAX from binding with these proteins. These results derived from effect of Deguelin on various cancer cell lines have further elucidated its role as a novel anti-tumorigenic agent targeting angiogenesis, apoptosis, cell proliferation and migration for cancer chemoprevention. In this review, an attempt has been made to highlight the potential therapeutic effects of Deguelin in destroying the cancer cells by inhibiting various tumour promoting pathways and its uses as a therapeutic agent alone or in combination.

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