The OTUD6B-LIN28B-MYC axis determines cell cycle progression in multiple myeloma
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ABSTRACT:
PROVIDER: PRJEB46352 | ENA |
REPOSITORIES: ENA
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Project description:Deubiquitylases (DUBs) remove ubiquitin from proteins. In the context of cancer, their inhibition can induce the degradation of oncoproteins, that may otherwise be “undruggable”. Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome and high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies. However, the role of DUBs in MM pathophysiology and therapy has remained elusive. Starting from genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B subsequent to LIN28B phosphorylation. LIN28B regulates miRNA biogenesis and exerts high expression in embryonic stem cells that becomes re-established in certain tumors, including MM. Binding of LIN28B at G1/S activates OTUD6B, which otherwise remains in a catalytically inactive state. As a consequence, stabilized LIN28B drives MYC expression via inhibition of let7 microRNAs, which in turn allows for a rapid transition of MM cells from G1 to S phase. Analyses of primary MM patient samples reveal a positive correlation of OTUDB6B expression with poor outcome, high MYC expression and MYC target gene induction, suggesting that high MYC levels in MM result from an activation of the OTUD6B-LIN28B nexus. Together, we here specify phosphorylation and cell cycle-dependent substrate binding as a means by which OTUD6B becomes activated to drive the G1/S transition via the LIN28B-MYC axis and nominate OTUD6B and LIN28B as actionable vulnerabilities in MM.
2022-10-12 | PXD027480 | Pride
Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome. Despite high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies, the role of Deubiquitylases (DUBs) in MM pathophysiology and therapy has remained elusive. Starting from genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B. RNA-Seq analyses reveal a significant downregulation of MYC target genes upon OTUD6B and LIN28B downregulation.
| PRJEB45829 | ENA
Project description:The goal was to determine the gene expression differences between CB-5083 and Bortezomib treated multiple myeloma cell lines Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system (UPS) and CB-5083, a first in class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematological and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma (MM) cell lines and a number of in vivo MM models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response (UPR) and apoptosis. CB-5083 decreases viability in MM cell lines and patient derived MM cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant MM models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with MM standard of care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several MM disease models and provide the rationale for clinical evaluation as monotherapy and in combination in MM.
2017-10-26 | GSE101923 | GEO
Project description:Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated protein Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into the intermembrane space of autophagosomes which fuse with secretory lysosomal-related organelles (LROs). Deletion of Plekhg5 in mice disrupts the secretion of these LROs causing Sod1 accumulation at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human isogenic iPSC-derived motoneurons we show an impaired secretion of ALS-linked SOD1D90A, which coincided with a reduced PLEKHG5 expression. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.
2024-08-28 | GSE269588 | GEO
Project description:Despite the extensive use of immunotherapies in hematological malignancies, the single-cell landscape of tumor infiltrating lymphocytes (TILs) in these patients lags behind what has been accomplished in solid tumors. One such example is multiple myeloma (MM), an incurable plasma cell malignancy for which treatment is being redefined by immunotherapies, while single-cell studies of TILs are scarce and the phenotype of tumor-reactive T cells remains unknown. Here we aimed at defining the phenotype of tumor-reactive T cells throughout myelomagenesis. To this end, we performed single-cell RNA and TCR sequencing of bone marrow T cells in MM and its precursor states, both in patients and experimental mouse models of spontaneous disease progression.
2023-08-05 | GSE205393 | GEO
Project description:MYC is a major oncogenic driver of Multiple Myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof-of-principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC dependent cancers as well.
2015-07-21 | GSE71100 | GEO
Project description:Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in transcriptome and develop de novo drug resistance. As a critical component in transcriptional regulation, how chromatin landscape is transformed in MM cells and regulates the transcriptional response to BMSCs remains elusive. We profiled 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 coexisting with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with accessibility increased at multiple regulatory sites were preferentially induced by BMSCs and enriched in response to drug and unfavorable prognostic markers from several MM patient cohorts. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulated the BMSC-induced transformation of regulome linked to the response to external stimuli. Together, we characterized BMSC-induced transcriptome and regulome signatures of MM cells and prioritized TFs for future study to depict epigenetic mechanisms of BMSC-induced drug resistance in MM.
2022-02-16 | GSE193657 | GEO
Project description:Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in transcriptome and develop de novo drug resistance. As a critical component in transcriptional regulation, how chromatin landscape is transformed in MM cells and regulates the transcriptional response to BMSCs remains elusive. We profiled 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 coexisting with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with accessibility increased at multiple regulatory sites were preferentially induced by BMSCs and enriched in response to drug and unfavorable prognostic markers from several MM patient cohorts. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulated the BMSC-induced transformation of regulome linked to the response to external stimuli. Together, we characterized BMSC-induced transcriptome and regulome signatures of MM cells and prioritized TFs for future study to depict epigenetic mechanisms of BMSC-induced drug resistance in MM.
2022-02-16 | GSE193656 | GEO
Project description:Multiple myeloma (MM), the second most common hematological malignancy, frequently relapses because of chemotherapeutic resistance. Fibroblast growth factors (FGFs) act as pro-angiogenic and mitogenic cytokines in MM. Here, we demonstrate that the FGF system is essential for MM cell survival by protecting MM cells from oxidative stress-induced apoptosis. Accordingly, extracellular FGF blockade by an FGF trapping approach causes proteasomal degradation of the c-Myc oncoprotein. This triggers mitochondrial oxidative stress, DNA damage and apoptosis in MM cell lines and MM cells from both naïve and relapsed/refractory patients. Our data highlight the mechanism by which the FGF system contributes to MM cell survival and disease progression, representing a therapeutic target for MM patients with poor prognosis and advanced disease stage.
2022-04-01 | GSE129279 | GEO
Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.
2023-01-25 | GSE214668 | GEO