Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due to development of resistance to therapy-elicited cell death. Nutrients are intricately connected to maintenance of ...cellular viability in part by inhibition of apoptosis. We were interested to determine if examination of metabolic regulation of BCL-2 proteins may provide insight on alternative routes to engage apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. We and others have demonstrated that glucose maintains levels of key resistance-promoting BCL-2 family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to survive in the absence of glucose or glutamine were found to maintain expression of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential mechanism for continued survival despite induction of BIM could be due to binding and sequestration of BIM to alternate pro-survival BCL-2 members. Our investigation revealed that cells surviving glutamine withdrawal in particular, enhance expression and binding of BIM to BCL-2, consequently sensitizing these cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization to venetoclax can be reversed by metabolic supplementation with TCA cycle intermediate α-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally enhanced with venetoclax treatment, however, targeting glutamine metabolism with 6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and relapse/refractory patient samples to venetoclax. Our studies reveal a potent therapeutic strategy of metabolically driven synthetic lethality involving targeting glutamine metabolism for sensitization to venetoclax in MM.
Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. The results suggest that venetoclax is only active in a ...small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in four of the five cell lines tested. The most striking results were seen with dexamethasone (Dex). Co-treatment of human myeloma cell lines and primary patient samples, with Dex and venetoclax, significantly increased cell death over venetoclax alone in four of the five cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of Dex. This results in alterations in Bim binding to anti-apoptotic proteins. Dex shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim-binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with Dex could be an effective therapy for a broader range of patients than would be predicted by single-agent activity.
The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics ...and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the 'primed' state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy.
Many health care organizations encourage frontline staff to pursue quality improvement (QI), local spread of those improvements, and publication of their work. Although much has been written about ...building and sustaining a culture of continuous QI, less is known about how to support success in QI rigor, credibility, spread, and publication. In this perspective article, we offer QI leaders practical suggestions to identify challenges in publishing QI and strategies to overcome these challenges. Health care organizations can assist QI teams with publication by intentionally formalizing scholarship early in their QI project work, providing accountability, and connecting the QI team to necessary resources. A carefully designed program supporting QI publication can both improve the rigor of QI work and enhance the professional development of QI professionals.
The Centers for Disease Control and Prevention (CDC) publishes COVID-19 non-pharmaceutical intervention (NPI) guidance for specific institutional audiences to limit community spread. Audiences ...include: business, clinical, public health, education, community, and state/local government. The swift, severe, and global nature of COVID-19 offers an opportunity to systematically obtain a national view of how larger institutions of higher education adopted NPI guidance at the onset of the pandemic.
An original database of COVID-19-related university NPI policy changes was compiled. Survey team members manually combed university websites and official statements capturing implementation decisions and dates for five NPI variables from 575 U.S. universities, across 50 states and the District of Columbia, during March of 2020. The universities included in this study were selected from the Department of Education Integrated Postsecondary Education Data System (IPEDS), which provides a set of university explanatory variables. Using IPEDS as the basis for the organizational data allows consistent mapping to event-time and institutional characteristic variables including public health announcements, geospatial, census, and political affiliation.
The dataset enables event-time analysis and offers a variety of variables to support institutional level study and identification of underlying biases like educational attainment. A descriptive analysis of the dataset reveals that there was substantial heterogeneity in the decisions that were made and the timing of these decisions as they temporally related to key state, national, and global emergency announcements. The WHO pandemic declaration coincided with the largest number of university decisions to implement NPIs.
This study provides descriptive observations and produced an original dataset that will be useful for future research focused on drivers and trends of COVID-19 NPIs for U.S. Universities. This preliminary analysis suggests COVID-19 university decisions appeared to be made largely at the university level, leading to major variations in the nature and timing of the responses both between and within states, which requires further study.
Growing opioid misuse in the United States has resulted in more children living with an adult with an opioid use history. Although an abundance of research has demonstrated a link between opioid ...misuse and negative parenting behaviors, few intervention efforts have been made to target this underserved population. The Family Check-Up (FCU) has been tested in more than 25 years of research, across multiple settings, and is an evidence-based program for reducing risk behavior, enhancing parenting skills, and preventing the onset of substance use. It is designed to motivate parents to engage in positive parenting practices and to change problematic parenting and has been tested across a variety of ages including early childhood and adolescence. It is highlighted in NIDA's Principles of Substance Use Prevention for Early Childhood: A research-based guide as one of only three effective selective prevention programs for substance abuse among families with young children. Recently, we developed an online version of the FCU that has now been adapted for early childhood and families with opioid use histories. The online platform and telehealth model allow for wide-scale dissemination, ease of training with community providers, and increased public health reach for families in remote, rural areas. This is particularly important when targeting families with opioid misuse and addiction because there are high rates of addiction in remote areas, yet few services available. In this article, we describe the FCU Online and review new content in the model that targets a population of young adult parents with substance abuse histories, including opioid use. New modules include content focused on harm reduction for this high-risk population of parents, such as safety in the home, substance use while parenting, and managing conflict with partners and friends.
The function and survival of normal and malignant plasma cells depends on the elaborately regulated ubiquitin proteasome system. Proteasome inhibitors such as bortezomib have proved to be highly ...effective in the treatment of multiple myeloma (MM), and their effects are related to normal protein homeostasis which is critical for plasma cell survival. Many ubiquitin ligases are regulated by conjugation with NEDD8. Therefore, neddylation may also impact survival and proliferation of malignant plasma cells. Here, we show that MLN4924, a potent NEDD8 activating enzyme (NAE) inhibitor, induced cytotoxicity in MM cell lines, and its antitumor effect is associated with suppression of the AKT and mammalian target of rapamycin (mTOR) signaling pathways through increased expression of REDD1. Combining MLN4924 with the proteasome inhibitor bortezomib induces synergistic apoptosis in MM cell lines which can overcome the prosurvival effects of growth factors such as interleukin-6 and insulin-like growth factor-1. Altogether, our findings demonstrate an important function for REDD1 in MLN4924-induced cytotoxicity in MM and also provide a promising therapeutic combination strategy for myeloma.
•Blockade of NAE and bortezomib induces phosphatidylinositol 3-kinase/mTOR inhibition.•NAE inhibition and bortezomib combined induce synergistic plasma cell apoptosis.
Multiple myeloma is highly dependent on the bone marrow microenvironment until progressing to very advanced extramedullary stages of the disease such as plasma cell leukemia. Stromal cells in the ...bone marrow secrete a variety of cytokines that promote plasma cell survival by regulating antiapoptotic members of the Bcl-2 family including Mcl-1, Bcl-xL, and Bcl-2. Although the antiapoptotic protein on which a cell depends is typically consistent among normal cells of a particular phenotype, Bcl-2 family dependence is highly heterogeneous in multiple myeloma. Although normal plasma cells and most multiple myeloma cells require Mcl-1 for survival, a subset of myeloma is codependent on Bcl-2 and/or Bcl-xL. We investigated the role of the bone marrow microenvironment in determining Bcl-2 family dependence in multiple myeloma. We used the Bcl-2/Bcl-xL inhibitor ABT-737 to study the factors regulating whether myeloma is Mcl-1 dependent, and thus resistant to ABT-737–induced apoptosis, or Bcl-2/Bcl-xL codependent, and thus sensitive to ABT-737. We demonstrate that bone marrow stroma is capable of inducing Mcl-1 dependence through the production of the plasma cell survival cytokine interleukin-6 (IL-6). IL-6 upregulates Mcl-1 transcription in a STAT3-dependent manner, although this occurred in a minority of the cells tested. In all cells, IL-6 treatment results in posttranslational modification of the proapoptotic protein Bim. Phosphorylation of Bim shifts its binding from Bcl-2 and Bcl-xL to Mcl-1, an effect reversed by MEK inhibition. Blocking IL-6 or downstream signaling restored Bcl-2/Bcl-xL dependence and may therefore represent a clinically useful strategy to enhance the activity of Bcl-2 inhibitors.
•Bone marrow stromal cell–derived IL-6 induces Mcl-1 dependence through transcriptional and posttranslational changes in the Bcl-2 family.•Blocking IL-6 signaling pathways sensitizes myeloma to inhibitors of Bcl-2 and Bcl-2/Bcl-xL.
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