Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

Guo, Wancheng; Wang, Haiqin; Chen, Peng; Shen, Xuedong; Zhang, Boxin; Liu, Jing; Peng, Hongling; Xiao, Xiaojuan

doi:10.3390/cancers13143523

Cited by 13 publications

(8 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In cancer cells, this kind of durable proliferation arrest or reversible “death” promotes post-therapy tumor repopulation, and is one of the main mechanisms that contribute to drug resistance [ 109 ]. In MM, misbehaving cells in active sleep refer to the multiple myeloma stem cell-like cells, which are believed to be the major cause of minimal residual disease [ 110 ]. MM cells of immature stem-like phenotypes tend to be more quiescent, which is linked to clinical drug resistance [ 111 ].…”

Section: MM Cell Survival and Ersrmentioning

confidence: 99%

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Wang

Fan

Sun

et al. 2022

Cancers

View full text Add to dashboard Cite

Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.

show abstract

Section: MM Cell Survival and Ersrmentioning

confidence: 99%

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Wang

Fan

Sun

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…In addition, the presence of rare subpopulations of tumor cells with stem cell-like properties like greater clonogenicity, self-renewal, and differentiation capacities, are believed to significantly contribute towards treatment-refractory phenotypes in various cancers, including myeloma ( 15 ). Since our previous study had shown that CLF erodes quiescent stem-cell populations (CD34+CD38-, CFSE-bright) in drug-resistant CML patients ( 10 ), we also showed that CLF kills quiescent/dormant cells, ALDH+ cells, and side populations (SPs), collectively referred to as putative stem-like cells in myeloma, with treatment-refractory phenotypes ( 16 – 19 ). We propose clinical efficacy studies in relapsed/refractory myeloma using clofazimine-based drug combination regimens.…”

Section: Introductionmentioning

confidence: 91%

Single-Cell Proteomics and Tumor RNAseq Identify Novel Pathways Associated With Clofazimine Sensitivity in PI- and IMiD- Resistant Myeloma, and Putative Stem-Like Cells

et al. 2022

View full text Add to dashboard Cite

Multiple myeloma (MM) is an incurable plasma cell malignancy with dose-limiting toxicities and inter-individual variation in response/resistance to the standard-of-care/primary drugs, proteasome inhibitors (PIs), and immunomodulatory derivatives (IMiDs). Although newer therapeutic options are potentially highly efficacious, their costs outweigh the effectiveness. Previously, we have established that clofazimine (CLF) activates peroxisome proliferator-activated receptor-γ, synergizes with primary therapies, and targets cancer stem-like cells (CSCs) in drug-resistant chronic myeloid leukemia (CML) patients. In this study, we used a panel of human myeloma cell lines as in vitro model systems representing drug-sensitive, innate/refractory, and clonally-derived acquired/relapsed PI- and cereblon (CRBN)-negative IMiD-resistant myeloma and bone marrow-derived CD138+ primary myeloma cells obtained from patients as ex vivo models to demonstrate that CLF shows significant cytotoxicity against drug-resistant myeloma as single-agent and in combination with PIs and IMiDs. Next, using genome-wide transcriptome analysis (RNA-sequencing), single-cell proteomics (CyTOF; Cytometry by time-of-flight), and ingenuity pathway analysis (IPA), we identified novel pathways associated with CLF efficacy, including induction of ER stress, autophagy, mitochondrial dysfunction, oxidative phosphorylation, enhancement of downstream cascade of p65-NFkB-IRF4-Myc downregulation, and ROS-dependent apoptotic cell death in myeloma. Further, we also showed that CLF is effective in killing rare refractory subclones like side populations that have been referred to as myeloma stem-like cells. Since CLF is an FDA-approved drug and also on WHO’s list of safe and effective essential medicines, it has strong potential to be rapidly re-purposed as a safe and cost-effective anti-myeloma drug.

show abstract

“…Cancer stem cells (CSC) are well-known for their quiescence, self-renewal, and drug-resistant capacity, contributing to tumor aggressiveness, treatment resistance, and tumor recurrence ( 181 ). However, the exact nature of this MM stem cell population, including the surface markers, is still largely debatable ( 182 ). Increasing evidence is indicating that dysregulation of the epigenetic machinery, including aberrant expression and/or mutations in DNA methylation modifiers, is playing a role in CSC maintenance in both solid and hematological cancers ( 183 ).…”

Section: Involvement Of Dna Methylation Modifiers In Normal Plasma Ce...mentioning

confidence: 99%

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

Muylaert

Hemelrijck²,

Maes³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called ‘epimutations’ have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.

show abstract

Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

Cited by 13 publications

References 119 publications

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

Single-Cell Proteomics and Tumor RNAseq Identify Novel Pathways Associated With Clofazimine Sensitivity in PI- and IMiD- Resistant Myeloma, and Putative Stem-Like Cells

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

Contact Info

Product

Resources

About