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HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [RNA-Seq]

ABSTRACT: Depletion of HRP2 induced remarkable resistance to PIs induced apoptosis of MM cells in vitro and in vivo, and suppressed expression of HRP2 was observed in bortezomib-resistant (BR) MM cells. Notably, HRP2 altered chemosensitivity more obviously in MM cells with t(4;14) translocation, and much remarkable resistant to PIs than other reagents. Moreover, HRP2 abolition of HRP2 augmented H3K27me3 modification, consequentially intensifying transcriptome alteration prone to cell survival and restriction of endoplasmic reticulum (ER) stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylases MYC-induced nuclear antigen (MINA) to degrade H3K27me3, released suppression on genes responsible for drug resistance, such as ATF3 and NR4A1. Thus, an EZH2 inhibitor, tazemetostat, synergistically sensitized anti-MM effect of bortezomib both in vitro and in vivo. Collectively, our study provides novel knowledge to understand the origination of chemoresistance in MM patients with t(4;14), and rationale for managing MM patients according to different genomic backgrounds.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166524 | GEO | 2021/02/11

REPOSITORIES: GEO

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HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors

Project description:HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors

| PRJNA701194 | ENA

NF-kB activation confers a prolonged event-free-survival in newly diagnosed myeloma patients harboring t(4;14) treated with bortezomib.

Project description:NF-kB pathway activation is the hallmark of hematological malignancies. In multiple myeloma (MM), a large variety of genomic alterations leading to either inactivation of repressor such as TRAF3, CYLD or cIAP1/2 or amplification of activators such as CD40 or NIK collectively contribute to frequently deregulate NF-kB signaling. In order to evaluate the prognostic impact of NF-kB mutations in MM, we performed a comprehensive analysis of a panel of newly diagnosed patients with cIAP1/2 biallelic deletion. We found that all patients have dysregulated NF-kB pathway and the majority of them presented t(4;14). Then we analyzed clinical outcome of 37 MM at presentation with t(4;14) and treated with bortezomib according to their NF-kB status. We showed that increase of NF-kB activity confers prolonged event-free survival. Altogether, our data suggest that NF-kB activation resulting from NF-kB mutations (ie cIAP1/2 deletion) or other mechanisms improves outcome of t(4;14)-positive MM treated with bortezomib.

2015-09-15 | GSE31272 | GEO

HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [RNA-Seq]

Project description:HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [RNA-Seq]

| PRJNA701198 | ENA

HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [ChIP-Seq]

Project description:HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [ChIP-Seq]

| PRJNA701200 | ENA

MMSET regulates transcription factors critical for survival of t(4;14) myeloma myeloma cells

2014-07-16 | GSE59424 | GEO

NSD2 interacts with SMARCA2 and regulates expression of oncogenes CCND1 and PRL3 in t(4;14) multiple myeloma

Project description:Recurrent chromosomal translocations are central to the pathogenesis of multiple myeloma (MM), with t(4;14) translocation being the second-most common and associated with poor prognosis. The nuclear receptor-binding SET domain 2 (NSD2) is overexpressed as a result of the translocation and has been suggested to be the primary oncogenic factor in t(4;14) MM. However, the detailed oncogenic mechanism of NSD2 in MM is still not completely understood. To address the relevant pathways downstream of NSD2 that contributes to myelomagenesis, SILAC-based mass-spectrometry analysis was used to determine NSD2-interacting proteins. We identified 74 proteins and in silico analysis showed that one of them, SMARCA2, interacts with NSD2. Comparison of SMARCA2 expression across MM cell lines with different translocation statuses showed that SMARCA2 was highly expressed in t(4;14) MM cells but not in non-t(4;14) MM cells. SMARCA2 knockdown in t(4;14) MM cells showed reduced cell growth and capacity to form colonies. We further investigated how NSD2 and SMARCA2 regulate the expressions of key myeloma genes, such as PRL3 and CCND1. This study reveals a spectrum of NSD2-interacting proteins involved in different biological pathways, indicating the importance of NSD2 in t(4;14) MM. The interaction between NSD2 and SMARCA2 in regulating the expression of CCND1 and PRL3 suggests the potential of SMARCA2 as a novel therapeutic target for t(4;14) MM.

2021-07-15 | GSE140860 | GEO

MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells

Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The translocation t(4;14)(p16;q32) is one of the most common translocation in MMs, affecting 15% of patients, and is associated with very poor prognosis. The histone methyltransferase (HMTase) MMSET is universally overexpressed in t(4;14) MM as a result of the t(4;14) translocation. MMSET is capable of producing 3 major isoforms, the full length MMSET II, short isoforms REIIBP and MMSET I. MMSET II has been suggested to play an important tumorigenic role in t(4;14) MM, but little is yet known about whether and how the MMSET short isoforms contribute to MM tumorigenesis. The aim of this study is to characterize MMSET I roles and determine its downstream targets in t(4;14) MM. In t(4;14) MM cells MMSET I knockdown with shRNAs induced cell apoptosis, reduced colony formation and inhibited tumorigenicity in vivo. We also found MMSET I knockdown decreased GLO1 expression, and ectopic MMSET I increased GLO1 expression, suggesting that MMSET I is an upstream regulator of GLO1. Further analysis indicated that MMSET I bound to GLO1 promoter region and depended on its C-terminus to regulate GLO1 expression. Our preliminary data suggested that MMSET I is an oncoprotein and could regulate GLO1 expression in t(4;14) multiple myeloma cells.

2019-01-01 | GSE98433 | GEO

MMSET regulates transcription factors critical for survival of t(4;14) myeloma myeloma cells

Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The multiple myeloma SET domain (MMSET), identified by its fusion to the IgH locus in t(4;14) MM, is universally overexpressed and has been suggested to play an important role in tumorigenicity in t(4;14) MM. In order to identify downstream functional targets of MMSET, we knocked down MMSET expression with shRNAs in KMS11, a t(4;14) MM cell line, and identified differentially expressed genes by gene expression microarray analysis. KMS11 cells were treated with shRNAs for 48 h. Total RNA was extracted by using the Qiagen RNeasy Mini kit (Germany). Gene expression was performed using the GeneChip Human Genome U133A Array (Affymetrix) following the manufacturerM-bM-^@M-^Ys instructions. Data analysis was performed using GeneSpring software from Agilent Technologies.

2014-07-16 | E-GEOD-59424 | biostudies-arrayexpress

A novel non-coding RNA within WHSC1 is over-expressed in t(4;14)-positive multiple myeloma and other cancers

Project description:We designed oligonucleotide tiling arrays spanning the t(4;14) breakpoint region on chromosome 4 to identify additional oncogenic RNAs in an unbiased fashion. Four (4) multiple myeloma bone marrow samples with t(4;14) and twelve (12) MM BM samples without t(4;14) were analyzed. Furthermore, seven (7) bladder (1 normal, 6 malignant), eight (8) colon (1 normal, 7 malignant) and eight (8) esophagus (2 normal, 6 maligant) tissue samples were analyzed. Finally, five (5) multiple myeloma cell line samples with t(4;14) - three (3) of LP-1 and two (2) of H929 - and three (3) MM cell line samples and three (3) non-MM cell line samples without t(4;14) - three (3) of U266 and three (3) of Hela - were analyzed.

2012-07-01 | E-GEOD-36685 | biostudies-arrayexpress

PKCα RNA-seq in t(4;14) cells

Project description:Multiple myeloma (MM) cells undergo metabolic reprogramming in response to a hypoxic and nutrient-deprived bone marrow microenvironment. However, it is unclear whether primary oncogenes in recurrent translocations drive metabolic heterogeneity that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase MMSET II that promotes plasma cell transformation through a global increase in H3K36me2. We identified PKCα as a novel epigenetic target that contributes to the oncogenic potential of MMSET II. RNA-sequencing of t(4;14) cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), is transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaces mitochondria-bound HK2 and reversed sensitivity towards the glycolytic blocker 3-Bromopyruvate. Additionally, we observed a metabolic shift to a less energetic state through the reduction in oxidative and glycolytic fluxes, resulting in an overall decrease in ATP production. We employed metabolomics and lactate emerged as a differential metabolite associated with PKCα. This conferred PKCα with immunomodulatory drug (IMiDs) resistance in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Altogether, we revealed novel insights into the epigenetic and metabolism crosstalk in MM and the opportunity for therapeutic intervention that leverages on the distinct metabolic program in t(4;14) myeloma.

2022-07-26 | GSE208739 | GEO

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