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Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244003 | GEO | 2023/09/25

REPOSITORIES: GEO

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Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [ChIP-seq]

Project description:Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiDs). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.

2023-09-25 | GSE244002 | GEO

Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [RNA-seq]

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Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma

Project description:Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma

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Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [ATAC-seq]

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Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [RNA-seq]

Project description:Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [RNA-seq]

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Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [ChIP-seq]

Project description:Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [ChIP-seq]

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Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma.

Project description:Increased levels of the nuclear export protein, exportin 1 (XPO1), were demonstrated in multiple myeloma (MM) patients. Targeting XPO1 with selinexor (the selective inhibitor of nuclear export; SINE compound KPT-330) demonstrates broad antitumor activity also in patient cells resistant to bortezomib; hence, it is a promising target in MM patients. Hypoxia is known to mediate tumor progression and drug resistance (including bortezomib resistance) in MM cells. In this study, we tested the effects of selinexor alone or in combination with bortezomib in normoxia and hypoxia on MM cell survival and apoptosis in vitro and in vivo. In vitro, selinexor alone decreased survival and increased apoptosis, resensitizing MM cells to bortezomib. In vivo, we examined the effects of selinexor alone on tumor initiation and tumor progression, as well as selinexor in combination with bortezomib, on tumor growth in a bortezomib-resistant MM xenograft mouse model. Selinexor, used as a single agent, delayed tumor initiation and tumor progression, prolonging mice survival. In bortezomib-resistant xenografts, selinexor overcame drug resistance, significantly decreasing tumor burden and extending mice survival when combined with bortezomib.

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Project description:Multiple myeloma (MM) drug resistance highlights a need for alternative therapeutic strategies. In this study, we show that CASIN, a selective inhibitor of cell division cycle 42 (Cdc42) GTPase, inhibited proliferation and survival of melphalan/bortezomib-resistant MM cells more profoundly than that of the sensitive cells. Furthermore, CASIN was more potent than melphalan/bortezomib in inhibiting melphalan/bortezomib-resistant cells. In addition, CASIN sensitized melphalan/bortezomib-resistant cells to this drug combination. Mechanistically, Cdc42 activity was higher in melphalan/bortezomib-resistant cells than that in the sensitive cells. CASIN inhibited mono-ubiquitination of Fanconi anemia (FA) complementation group D2 (FANCD2) of the FA DNA damage repair pathway in melphalan-resistant but not melphalan-sensitive cells, thereby sensitizing melphalan-resistant cells to DNA damage. CASIN suppressed epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and extracellular signal-regulated kinase (ERK) activities to a larger extent in bortezomib-resistant than in melphalan-sensitive cells. Reconstitution of ERK activity partially protected CASIN-treated bortezomib-resistant cells from death, suggesting that CASIN-induced killing is attributable to suppression of ERK. Importantly, CASIN extended the lifespan of mouse xenografts of bortezomib-resistant cells and caused apoptosis of myeloma cells from bortezomib-resistant MM patients. Finally, CASIN had negligible side effects on peripheral blood mononuclear cells (PBMC) from healthy human subjects and normal B cells. Our data provide a proof of concept demonstration that rational targeting of Cdc42 represents a promising approach to overcome MM drug resistance.

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Super-Enhancer Associated Five-Gene Risk Score Model Predicts Overall Survival in Multiple Myeloma Patients.

Project description:Multiple myeloma (MM) is a malignant plasma cell tumor with high heterogeneity, characterized by anemia, hypercalcemia, renal failure, and lytic bone lesions. Although various powerful prognostic factors and models have been exploited, the development of more accurate prognosis and treatment for MM patients is still facing many challenges. Given the essential roles of super-enhancer (SE) associated genes in the tumorigenesis of MM, we tried to initially screen and identify the significant prognostic factors from SE associated genes in MM by the least absolute shrinkage and selection operator (Lasso) penalized Cox regression, univariate and multivariate Cox regression analysis using GSE24080 and GSE9782 datasets. Risk score model of five genes including CSGALNACT1, FAM53B, TAPBPL, REPIN1, and DDX11, was further constructed and the Kaplan-Meier (K-M) curves showed that the low-risk group seems to have better clinical outcome of survival compared to the high-risk group. Time-dependent receiver operating characteristic (ROC) curves presented the favorable performance of the model. An interactive nomogram consisting of the five-gene risk group and eleven clinical traits was established and identified by calibration curves. Therefore, the risk score model of SE associated five genes developed here could be used to predict the prognosis of MM patients, which may assist the clinical treatment of MM patients in the future.

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