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The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches. Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD). [ABSTRACT FROM AUTHOR]

Background: Emerging data suggest variability in susceptibility and outcome to coronavirus disease 2019 (COVID-19) infection. Identifying risk factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations.Methods: We analyzed electronic health records of the US Veterans Affairs Healthcare System and assessed the prevalence of COVID-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for COVID-19 who were positive, as well as outcome attributable to COVID-19, and stratified by clinical characteristics including demographics, comorbidities, cancer treatment, and cancer type. All statistical tests are 2-sided.Results: Of 22 914 cancer patients tested for COVID-19, 1794 (7.8%) were positive. The prevalence of COVID-19 was similar across age. Higher prevalence was observed in African American (15.0%) compared with White (5.5%; P < .001) and in patients with hematologic malignancy compared with those with solid tumors (10.9% vs 7.8%; P < .001). Conversely, prevalence was lower in current smokers and patients who recently received cancer therapy (<6 months). The COVID-19-attributable mortality was 10.9%. Higher attributable mortality rates were observed in older patients, those with higher Charlson comorbidity score, and in certain cancer types. Recent (<6 months) or past treatment did not influence attributable mortality. Importantly, African American patients had 3.5-fold higher COVID-19-attributable hospitalization; however, they had similar attributable mortality as White patients.Conclusion: Preexistence of cancer affects both susceptibility to COVID-19 infection and eventual outcome. The overall COVID-19-attributable mortality in cancer patients is affected by age, comorbidity, and specific cancer types; however, race or recent treatment including immunotherapy do not impact outcome. [ABSTRACT FROM AUTHOR]

Summary The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy. Graphical Abstract Highlights • E2F1 and its heterodimerization partner DP1 are required for myeloma cell proliferation • E2F1-DP1 heterodimers regulate promoter proximal transcription • E2F1 and BRD4 establish distinct regulatory axes in multiple myeloma • Combined inhibition of BRD4 and E2F co-operatively reduces myeloma tumor growth Uncontrolled proliferation is a hallmark of tumorigenesis and is associated with perturbed transcriptomic profile. Fulciniti et al. explored the interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma, reporting the existence of two distinct regulatory axes that can be synergistically targeted to impact myeloma growth and survival. [ABSTRACT FROM AUTHOR]