BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Gupta, Vikas A.; Ackley, James C.; Kaufman, Jonathan L.; Boise, Lawrence H.

doi:10.2147/blctt.s245191

Cited by 16 publications

(17 citation statements)

References 84 publications

(132 reference statements)

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“…Apart from that, differential expression of genes involved in NF-κB pathway were identified ( NFKBIB , IKBKB , CARD11 , TNFRSF1A , MAP3K1 , MAP3K14 and TLR4 ) suggesting the important role of NF-κB pathway in myelomagenesis (Chapman et al 2011 ). Aberrant expression of apoptosis-related genes such as BCL2 , BIK and BAX were also detected in the current study (Gupta et al 2021 ). Additionally, the most established growth factors and cytokines involved in bone marrow microenvironment, namely IL6 and IGF1 , were found to be over-expressed in the MM vs. control group in this study (Birmann et al 2009 ).…”

Section: Discussionsupporting

confidence: 83%

Gene expression profiling and in vitro functional studies reveal RAD54L as a potential therapeutic target in multiple myeloma

Othman

et al. 2022

Genes Genom

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Background Current advances in the molecular biology of multiple myeloma (MM) are not sufficient to fully delineate the genesis and development of this disease. Objective This study aimed to identify molecular targets underlying MM pathogenesis. Methods mRNA expression profiling for 29 samples (19 MM samples, 7 MM cell lines and 3 controls) were obtained using microarray. We evaluated the in vitro effects of RAD54L gene silencing on the proliferation, apoptosis and cell cycle distribution in KMS-28BM human MM cells using siRNA approach. Cell proliferation was determined by MTS assay while apoptosis and cell cycle distribution were analysed with flow cytometry. Gene and protein expression was evaluated using RT-qPCR and ELISA, respectively. Results Microarray results revealed a total of 5124 differentially expressed genes (DEGs), in which 2696 and 2428 genes were up-regulated and down-regulated in MM compared to the normal controls, respectively (fold change ≥ 2.0; P < 0.05). Up-regulated genes (RAD54L, DIAPH3, SHCBP1, SKA3 and ANLN) and down-regulated genes (HKDC1, RASGRF2, CYSLTR2) have never been reported in association with MM. Up-regulation of RAD54L was further verified by RT-qPCR (P < 0.001). In vitro functional studies revealed that RAD54L gene silencing significantly induced growth inhibition, apoptosis (small changes) and cell cycle arrest in G0/G1 phase in KMS-28BM (P < 0.05). Silencing of RAD54L also decreased its protein level (P < 0.05). Conclusions This study has identified possible molecular targets underlying the pathogenesis of MM. For the first time, we reveal RAD54L as a potential therapeutic target in MM, possibly functioning in the cell cycle and checkpoint control.

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Section: Discussionsupporting

confidence: 83%

Gene expression profiling and in vitro functional studies reveal RAD54L as a potential therapeutic target in multiple myeloma

Othman

et al. 2022

Genes Genom

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“…Conversely, MCL1, BCLW, BCLXL, BFL1, and BCL2 are the main anti-apoptotic proteins. The balance of pro- and anti-apoptotic proteins affects cell fate, which varies between cells ( 46 ).…”

Section: Translocation T(11;14) and Bcl2 Protein Family Codependencymentioning

confidence: 99%

“…MM with t(11;14) has distinct biology with considerably increased BCL2 and decreased MCL1 expression ( 44 , 60 ). Due to high BCL2 expression, patients with t(11;14) are dependent on anti-apoptotic BCL2 proteins ( 46 , 58 ). The rationale behind the response to BCL2 inhibitors is that malignant cells exhibit anti-apoptotic properties to survive.…”

Section: Translocation T(11;14) and Bcl2 Protein Family Codependencymentioning

confidence: 99%

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation

2022

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Multiple myeloma (MM) is a genetically complex disease. The key myeloma-initiating genetic events are hyperdiploidy and translocations involving the immunoglobulin heavy chain (IgH) enhancer on chromosome 14, which leads to the activation of oncogenes (e.g., CCND1, CCND3, MAF, and MMSET). The t(11;14) translocation is the most common in MM (15%–20%) and results in cyclin D1 (CCND1) upregulation, which leads to kinase activation and tumor cell proliferation. Notably, t(11;14) occurs at a higher rate in patients with plasma cell leukemia (40%) and light chain amyloidosis (50%). Patients with myeloma who harbor the t(11;14) translocation have high levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2). Multiple studies demonstrated that the presence of t(11;14) was predictive of BCL2 dependency, suggesting that BCL2 could be a target in this subtype of myeloma. Venetoclax, an oral BCL2 inhibitor, has shown remarkable activity in treating relapsed/refractory MM patients with t(11;14) and BCL2 overexpression, either as monotherapy or in combination with other anti-myeloma agents. In this review, we describe the molecular defects associated with the t(11;14), bring into question the standard cytogenetic risk of myeloma patients harboring t(11;14), summarize current efficacy and safety data of targeted venetoclax-based therapies, and discuss the future of individualized or precision medicine for this unique myeloma subgroup, which will guide optimal treatment.

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“…The anti-apoptotic proteins BCL2, MCL-1, and BCL-XL (BCL2L1) are expressed in MM cells [100]. Increased expression, particularly of MCL-1 and BCL-XL, is associated with worse patient outcome.…”

Section: Possible 1q21 Targets Genes Outside Of Chromosome 1qmentioning

confidence: 99%

Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

Burroughs‐Garcia

Eufemiese

Storti

et al. 2021

Cells

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Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon.

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BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Cited by 16 publications

References 84 publications

Gene expression profiling and in vitro functional studies reveal RAD54L as a potential therapeutic target in multiple myeloma

Gene expression profiling and in vitro functional studies reveal RAD54L as a potential therapeutic target in multiple myeloma

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation

Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

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