skip to main content


Title: Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma
Multiple myeloma (MM) is a plasma cells neoplasm. The overexpression of Bcl-2 family proteins, particularly myeloid cell leukemia 1 (Mcl-1), plays a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis of MM. Thus, inhibition of the Mcl-1 protein considered as a therapeutic strategy to kill the myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. This review presents the critical role of Mcl-1 in the progression of MM, the most prominent BH3 mimetic and semi-BH3 mimetic that selectively inhibit Mcl-1, and could be used as single agent or combined with existing therapies.  more » « less
Award ID(s):
1827938
NSF-PAR ID:
10298719
Author(s) / Creator(s):
; ; ; ; ; ; ; ;
Date Published:
Journal Name:
Frontiers in Pharmacology
Volume:
12
ISSN:
1663-9812
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in the transcriptome and develop de novo multi-drug resistance. As a critical component in transcriptional regulation, how the chromatin landscape is transformed in MM cells exposed to BMSCs and contributes to the transcriptional response to BMSCs remains elusive. We profiled the transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells that coexisted with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in the JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with increasing accessibility at multiple regulatory sites were preferentially induced by BMSCs; these genes were enriched in functions linked to responses to drugs and unfavorable clinic outcomes. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulate the BMSC-induced transformation of the regulome linked to the transcriptional response. Together, we characterized the BMSC-induced transcriptome and regulome signatures of MM cells to facilitate research on epigenetic mechanisms of BMSC-induced multi-drug resistance in MM. 
    more » « less
  2. null (Ed.)
    Abstract Background Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo. Methods To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2 V617F –driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2 V617F –driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis. Results We found that JAK2 V617F -mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2 V617F -mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2 V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2 V617F -driven MPN. Conclusion LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2 V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2 V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2 V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN. 
    more » « less
  3. Abstract

    The RNA exosome is a conserved molecular machine that processes/degrades numerous coding and non-coding RNAs. The 10-subunit complex is composed of three S1/KH cap subunits (human EXOSC2/3/1; yeast Rrp4/40/Csl4), a lower ring of six PH-like subunits (human EXOSC4/7/8/9/5/6; yeast Rrp41/42/43/45/46/Mtr3), and a singular 3′-5′ exo/endonuclease DIS3/Rrp44. Recently, several disease-linked missense mutations have been identified in structural cap and core RNA exosome genes. In this study, we characterize a rare multiple myeloma patient missense mutation that was identified in the cap subunit gene EXOSC2. This missense mutation results in a single amino acid substitution, p.Met40Thr, in a highly conserved domain of EXOSC2. Structural studies suggest that this Met40 residue makes direct contact with the essential RNA helicase, MTR4, and may help stabilize the critical interaction between the RNA exosome complex and this cofactor. To assess this interaction in vivo, we utilized the Saccharomyces cerevisiae system and modeled the EXOSC2 patient mutation into the orthologous yeast gene RRP4, generating the variant rrp4-M68T. The rrp4-M68T cells show accumulation of certain RNA exosome target RNAs and show sensitivity to drugs that impact RNA processing. We also identified robust negative genetic interactions between rrp4-M68T and specific mtr4 mutants. A complementary biochemical approach revealed that Rrp4 M68T shows decreased interaction with Mtr4, consistent with these genetic results. This study suggests that the EXOSC2 mutation identified in a multiple myeloma patient impacts the function of the RNA exosome and provides functional insight into a critical interface between the RNA exosome and Mtr4.

     
    more » « less
  4. We present the analysis of defective pathways in multiple myeloma (MM) using two recently developed sampling algorithms of the biological pathways: The Fisher’s ratio sampler, and the holdout sampler. We performed the retrospective analyses of different gene expression datasets concerning different aspects of the disease, such as the existing difference between bone marrow stromal cells in MM and healthy controls (HC), the gene expression profiling of CD34+ cells in MM and HC, the difference between hyperdiploid and non-hyperdiploid myelomas, and the prediction of the chromosome 13 deletion, to provide a deeper insight into the molecular mechanisms involved in the disease. Our analysis has shown the importance of different altered pathways related to glycosylation, infectious disease, immune system response, different aspects of metabolism, DNA repair, protein recycling and regulation of the transcription of genes involved in the differentiation of myeloid cells. The main difference in genetic pathways between hyperdiploid and non-hyperdiploid myelomas are related to infectious disease, immune system response and protein recycling. Our work provides new insights on the genetic pathways involved in this complex disease and proposes novel targets for future therapies. 
    more » « less
  5. Organ formation requires precise regulation of cell cycle and morphogenetic events. Using theDrosophilaembryonic salivary gland (SG) as a model, we uncover the role of the SP1/KLF transcription factor Huckebein (Hkb) in coordinating cell cycle regulation and morphogenesis. Thehkbmutant SG exhibits defects in invagination positioning and organ size due to the abnormal death of SG cells. Normal SG development involves distal-to-proximal progression of endoreplication (endocycle), whereashkbmutant SG cells undergo abnormal cell division, leading to cell death. Hkb represses the expression of key cell cycle and pro-apoptotic genes in the SG. Knockdown ofcyclin Eorcyclin-dependent kinase 1,or overexpression offizzy-relatedrescues most of the morphogenetic defects observed in thehkbmutant SG. These results indicate that Hkb plays a critical role in controlling endoreplication by regulating the transcription of key cell cycle effectors to ensure proper organ formation.

     
    more » « less