Integrative multi-omics identifies high risk multiple myeloma subgroup associated with significant DNA loss and dysregulated DNA repair and cell cycle pathways

Ortiz-Estévez, María; Towfic, Fadi; Flynt, Erin; Stong, Nicholas; Jang, In Sock; Wang, Kai; Trotter, Matthew; Thakurta, Anjan

doi:10.1186/s12920-021-01140-5

Cited by 5 publications

(7 citation statements)

References 59 publications

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“…Our previous study indicated that cell adhesion is inhibited and EMT is enhanced in MM patients 16 . However, the role of E2F2 in the pathogenicity of MM in general and its involvement in MM cell adhesion in particular was explored only by a few studies 29,30 . In this study, we found that aberrant E2F2 expression was closely associated with poor prognosis and advanced clinical stages in MM patients.…”

Section: Discussionmentioning

confidence: 60%

“…16 However, the role of E2F2 in the pathogenicity of MM in general and its involvement in MM cell adhesion in particular was explored only by a few studies. 29,30 In this study, we found that aberrant E2F2 expression was closely associated with poor prognosis and advanced clinical stages in MM patients. Concurrently, we discovered that E2F2 was significantly highly expressed in MM cells and enhanced EMT and cell migration.…”

Section: Discussionmentioning

confidence: 62%

“…28 A few studies have reported that activated E2F2 participates in DNA repair and cell cycle regulation in MM. 29,30 Currently, the role of E2F2 in the adhesion of MM cells, as well as the underlying mechanism, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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E2F2 modulates cell adhesion through the transcriptional regulation of PECAM1 in multiple myeloma

Chen

Mai

et al. 2023

Br J Haematol

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SummaryMultiple myeloma (MM) is the second most common haematological malignancy. Despite the development of new drugs and treatments in recent years, the therapeutic outcomes of patients are not satisfactory. It is necessary to further investigate the molecular mechanism underlying MM progression. Herein, we found that high E2F2 expression was correlated with poor overall survival and advanced clinical stages in MM patients. Gain‐ and loss‐of‐function studies showed that E2F2 inhibited cell adhesion and consequently activated cell epithelial‐to‐mesenchymal transition (EMT) and migration. Further experiments revealed that E2F2 interacted with the PECAM1 promoter to suppress its transcriptional activity. The E2F2‐knockdown‐mediated promotion of cell adhesion was significantly reversed by the repression of PECAM1 expression. Finally, we observed that silencing E2F2 significantly inhibited viability and tumour progression in MM cell models and xenograft mouse models respectively. This study demonstrates that E2F2 plays a vital role as a tumour accelerator by inhibiting PECAM1‐dependent cell adhesion and accelerating MM cell proliferation. Therefore, E2F2 may serve as a potential independent prognostic marker and therapeutic target for MM.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 62%

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E2F2 modulates cell adhesion through the transcriptional regulation of PECAM1 in multiple myeloma

Chen

Mai

et al. 2023

Br J Haematol

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“…Patient-level transcriptomic data and clinical information, including cytogenetics and progression/survival outcomes, were assessed. RNA extraction, library preparation, and sequencing for the Multiple Myeloma Research Foundation (MMRF), CC-4047-MM-010 and CC-220-MM-001, have been described previously ( Walker et al, 2018 ; Gooding et al, 2021 ; Ortiz Estevez et al, 2021 ). NDMM patient data from the MMRF (N = 348) was used as discovery, and Toulouse [ N = 127, all t(4:14) patients] as replication cohorts.…”

Section: Methodsmentioning

confidence: 99%

Multiple Myeloma Patient Tumors With High Levels of Cereblon Exon-10 Deletion Splice Variant Upregulate Clinically Targetable Pro-Inflammatory Cytokine Pathways

et al. 2022

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Immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide, are used in the routine treatment for multiple myeloma (MM) patients. Cereblon (CRBN) is the direct molecular target of IMiDs. While CRBN is not an essential gene for MM cell proliferation, the frequency of CRBN genetic aberrations, including mutation, copy number loss, and exon-10 (which includes a portion of the IMiD-binding domain) splicing, have been reported to incrementally increase in later-line patients. CRBN exon-10 splicing has also been shown to be associated with decreased progression-free survival in both newly diagnosed and relapsed refractory MM patients. Although we did not find significant general splicing defects among patients with CRBN exon-10 splice variant when compared to those expressing the full-length transcript, we identified upregulated TNFA signaling via NFKB, inflammatory response, and IL-10 signaling pathways in patients with exon-10 splice variant across various data sets—all potentially promoting tumor growth via chronic growth signals. We examined master regulators that mediate transcriptional programs in CRBN exon-10 splice variant patients and identified BATF, EZH2, and IKZF1 as the key candidates across the four data sets. Upregulated downstream targets of BATF, EZH2, and IKZF1 are components of TNFA signaling via NFKB, IL2/STAT5 signaling pathways, and IFNG response pathways. Previously, BATF-mediated transcriptional regulation was associated with venetoclax sensitivity in MM. Interestingly, we found that an EZH2 sensitivity gene expression signature also correlated with high BATF or venetoclax sensitivity scores in these tumors. Together, these data provide a rationale for investigating EZH2 inhibitors or venetoclax in combination with the next generation CRBN-targeting agents, such as CELMoDs, for patients overexpressing the CRBN exon-10 splice variant.

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“… 6 , 7 Gene expression signatures have also been shown to transition to those that indicate higher risk as disease progresses. 8 …”

Section: Introductionmentioning

confidence: 99%

Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma

Ansari-Pour

Samur

Flynt

et al. 2023

Blood

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Large-scale analyses of genomic data from newly-diagnosed multiple myeloma patients (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory multiple myeloma (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole genome sequencing (WGS) data from 418 tumors (386 patients) derived from six rrMM clinical trials and compared them with WGS from 198 unrelated ndMM patients in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), non-coding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNA; 1qGain, 17pLOH) and double-hit events (Amp1q-ISS3, 1qGain-17pLOH). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiDsÒ)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain and 17pLOH increased in prevalence from ndMM to lenalidomide (LEN)- to pomalidomide (POM)-resistant stages while enrichment of MAML3 along with IGL and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be evaluated further in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.

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Integrative multi-omics identifies high risk multiple myeloma subgroup associated with significant DNA loss and dysregulated DNA repair and cell cycle pathways

Cited by 5 publications

References 59 publications

E2F2 modulates cell adhesion through the transcriptional regulation of PECAM1 in multiple myeloma

E2F2 modulates cell adhesion through the transcriptional regulation of PECAM1 in multiple myeloma

Multiple Myeloma Patient Tumors With High Levels of Cereblon Exon-10 Deletion Splice Variant Upregulate Clinically Targetable Pro-Inflammatory Cytokine Pathways

Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma

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