Multiple Myeloma Relapse Is Associated with Increased NFκB Pathway Activity and Upregulation of the Pro-Survival BCL-2 Protein BFL-1

Spaan, Ingrid; Stolpe, Anja van de; Raymakers, Reinier; Peperzak, Victor

doi:10.3390/cancers13184668

Cited by 8 publications

(6 citation statements)

References 39 publications

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“…However, BCL2A1 is overexpressed in a variety of cancer cells (Vogler 2012). In a recent study, it is reported that disease relapse in MM is related to increased NFκB pathway activity, which causes increased BCL2A1 expression (Spaan et al 2021). Considering the upregulated BCL2A1 expression in young MM patients, it can be hypothesized that BCL2A1 may be a target for treatment with the current anti-cancer drug obatoklax mesylate currently used in acute myeloid leukemia and lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Transcriptomic Changes in Younger and Older Multiple Myeloma Patients from the MMRF-CoMMpass Study RNA-Seq Data

Keskin

2022

Preprint

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Background: Age-related differences in Multiple Myeloma (MM) are studied in clinical and genomic context, however, transcriptome changes have not yet been determined. The aim of this study is to identify the genes that are expressed differently in young and old patient groups and to examine the relationship of these genes with biological pathways and the drugs that can be used. Methods: The MMRF CoMMpass cohort RNA-Seq data (n=634) was used to analyze differen-tially expressed genes between young and old patients. GO term and KEGG gene-set enrichment analysis were conducted using R packages. Drug-gene interactions were detected using DGIdb. Results: Globally, 523 genes (366 upregulated, 157 downregulated) were differentially expressed (p < 0.05) in young patients. Totally 220 GO terms, mostly related to immune regulation path-ways were enriched. Cytokine-cytokine receptor interaction gene-set was enriched in KEGG GSEA. Among the highest expression difference, genes involved in immune regulation (FCGR1A, FCER1G, TLR2), known proto-oncogenic genes (BCL2, FGR) and genes under in-vestigation for association with various cancers (RGL4, MT-RNR1, ETS2, ENPP3, FUT7, NTNG2, PRAM1) were identified. Drugs associated with the pathways affected by these genes were identified. Conclusions: Further investigation of differentially expressed genes in young patients may shed light on new treatment options.

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Section: Discussionmentioning

confidence: 99%

Comparison of Transcriptomic Changes in Younger and Older Multiple Myeloma Patients from the MMRF-CoMMpass Study RNA-Seq Data

Keskin

2022

Preprint

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“…From a gene transcript expression analysis of eight primary multiple myeloma patient samples that relapsed after chemotherapy, BCL2A1 was identified as the most frequently increased factor, suggesting its therapy resistant role in multiple myeloma [ 60 ].…”

Section: Bfl-1 In Drug Resistancementioning

confidence: 99%

Last but not least: BFL-1 as an emerging target for anti-cancer therapies

Wang

Diepstraten

Herold

2022

Biochemical Society Transactions

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BFL-1 is an understudied pro-survival BCL-2 protein. The expression of BFL-1 is reported in many cancers, but it is yet to be clarified whether high transcript expression also always correlates with a pro-survival function. However, recent applications of BH3-mimetics for the treatment of blood cancers identified BFL-1 as a potential resistance factor in this type of cancer. Hence, understanding the role of BFL-1 in human cancers and how its up-regulation leads to therapy resistance has become an area of great clinical relevance. In addition, deletion of the murine homologue of BFL-1, called A1, in mice showed only minimal impacts on the well-being of these animals, suggesting drugs targeting BFL-1 would exhibit limited on-target toxicities. BFL-1 therefore represents a good clinical cancer target. Currently, no effective BFL-1 inhibitors exist, which is likely due to the underappreciation of BFL-1 as a potential target in the clinic and lack of understanding of the BFL-1 protein. In this review, the roles of BFL-1 in the development of different types of cancers and drug resistant mechanisms are discussed and some recent advances in the generation of BFL-1 inhibitors highlighted.

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“…Functional profiling of BCL2 dependence can also predict clinical response in MM, as an alternative approach to precision medicine that utilizes preclinical BH3 profiling and ex vivo testing with venetoclax to determine what level of ex vivo drug sensitivity is associated with clinical response ( 115 ). Furthermore, disease relapse after treatment resulted in increased NFkB activity and increased BCL2A1 (coding for BFL-1) as well as Bcl-2 and Bcl-xL ( 128 ).…”

Section: Venetoclax Sensitivity In MMmentioning

confidence: 99%

Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance

Saldarriaga¹,

Darwiche²,

Jayabalan³

et al. 2022

Front. Oncol.

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Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with “progressor” MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly preserved clonal heterogeneity seen upon progression of SMM, combined with the importance of these early variables, suggests that the identification of progressors based on these findings could complement and enhance the currently available clinical models based on tumor burden. Mechanisms leading to relapse/refractory multiple myeloma (RRMM) are of clinical interest given worse overall survival in this population. An Increased mutational burden is seen in patients with RRMM when compared to NDMM, however, there is evidence of branching evolution with many of these mutations being present at the subclonal level. Likewise, alterations in proteins associated with proteosome inhibitor and immunomodulatory drugs activity could partially explain clinical resistance to these agents. Evidence of chromosomal events leading to copy number changes is seen, with the presence of TP53 deletion, mutation, or a combination of both being present in many cases. Additional chromosomal events such as 1q gain and amplification may also interact and lead to resistance.

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Multiple Myeloma Relapse Is Associated with Increased NFκB Pathway Activity and Upregulation of the Pro-Survival BCL-2 Protein BFL-1

Cited by 8 publications

References 39 publications

Comparison of Transcriptomic Changes in Younger and Older Multiple Myeloma Patients from the MMRF-CoMMpass Study RNA-Seq Data

Comparison of Transcriptomic Changes in Younger and Older Multiple Myeloma Patients from the MMRF-CoMMpass Study RNA-Seq Data

Last but not least: BFL-1 as an emerging target for anti-cancer therapies

Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance

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