Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing

Cohen, Yaël; Zada, Mor; Wang, Shuang-Yin; Bornstein, Chamutal; David, Eyal; Moshe, Adi; Li, Baoguo; Shlomi-Loubaton, Shir; Gatt, Moshe E.; Gur, Chamutal; Lavi, Noa; Ganzel, Chezi; Luttwak, Efrat; Chubar, Evgeni; Rouvio, Ory; Vaxman, Iuliana; Pasvolsky, Oren; Ballan, Mouna; Tadmor, Tamar; Nemets, Anatoly; Jarchowcky-Dolberg, Osnat; Shvetz, Olga; Laiba, Meirav; Shpilberg, Ofer; Dally, Najib; Avivi, Irit; Weiner, Assaf; Amit, Ido

doi:10.1038/s41591-021-01232-w

Cited by 166 publications

(165 citation statements)

References 52 publications

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“…Overexpression of S100A4 conferred human cancer cell lines resistant to the chemotherapeutic drug methotrexate (Mencía et al, 2010) and suppression of the S100A4 gene increased sensitivity of pancreatic cancer cells to gemcitabine treatment (Mahon et al, 2007). In a recent study, S100A4 showed significant upregulation in MM non-responding vs. responding patients treated with KARA-KRD (Cohen et al, 2021). These studies indicate the potential role of S100A4 gene in MM progression and drug response, and suppression of S100A4 gene may contribute to a novel therapeutic approach for MM treatment.…”

Section: Discussionmentioning

confidence: 89%

“…Some S100 proteins (S100A3, S100A9, S100A12, and S100A13) were upregulated in normal plasma cells compared with MM cells (Zhan et al, 2002;Amit et al, 2021). In a recent study, S100A4, S100A10, and S100A11 showed significant upregulation in MM nonresponding versus responding patients treated with a combined regimen, including daratumumab, carfilzomib, lenalidomide, and dexamethasone (KARA-KRD), and their overexpression were also involved in clonal evolution of a primary refractory MM patient responding to KARA-KRD treatment (Cohen et al, 2021). Although S100 proteins are known to contribute to cancer progression and drug resistance, their functions in MM and possible effects on treatment response remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

Liu

Wang

Miettinen

et al. 2021

Front. Cell Dev. Biol.

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Despite several new therapeutic options, multiple myeloma (MM) patients experience multiple relapses and inevitably become refractory to treatment. Insights into drug resistance mechanisms may lead to the development of novel treatment strategies. The S100 family is comprised of 21 calcium binding protein members with 17 S100 genes located in the 1q21 region, which is commonly amplified in MM. Dysregulated expression of S100 family members is associated with tumor initiation, progression and inflammation. However, the relationship between the S100 family and MM pathogenesis and drug response is unknown. In this study, the roles of S100 members were systematically studied at the copy number, transcriptional and protein level with patients’ survival and drug response. Copy number analysis revealed a predominant pattern of gains occurring in S100 genes clustering in the 1q21 locus. In general, gains of genes encoding S100 family members associated with worse patient survival. However, S100 gene copy number and S100 gene expression did not necessarily correlate, and high expression of S100A4 associated with poor patient survival. Furthermore, integrated analysis of S100 gene expression and ex vivo drug sensitivity data showed significant negative correlation between expression of S100 family members (S100A8, S100A9, and S100A12) and sensitivity to some drugs used in current MM treatment, including proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) and histone deacetylase inhibitor panobinostat. Combined proteomic and pharmacological data exhibited significant negative association of S100 members (S100A4, S100A8, and S100A9) with proteasome inhibitors and panobinostat. Clinically, the higher expression of S100A4 and S100A10 were significantly linked to shorter progression free survival in patients receiving carfilzomib-based therapy. The results indicate an association and highlight the potential functional importance of S100 members on chromosome 1q21 in the development of MM and resistance to established myeloma drugs, including proteasome inhibitors.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

Liu

Wang

Miettinen

et al. 2021

Front. Cell Dev. Biol.

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“…More recently, the scRNAseq methodology has been applied in a clinical trial to study the dynamics of MM resistance mechanisms in highly resistant MM patients. Interestingly, the study revealed new, potentially druggable resistance mechanisms and therefore opened new possibilities for clinical utilization of modern advances in high-resolution sequencing technologies [ 96 ].…”

Section: Methodological Limitations Of Clonal Evolution Studies In Multiple Myelomamentioning

confidence: 99%

Clonal Evolution of Multiple Myeloma—Clinical and Diagnostic Implications

2021

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Plasma cell dyscrasias are a heterogeneous group of diseases characterized by the expansion of bone marrow plasma cells. Malignant transformation of plasma cells depends on the continuity of events resulting in a sequence of well-defined disease stages, from monoclonal gammopathy of undetermined significance (MGUS) through smoldering myeloma (SMM) to symptomatic multiple myeloma (MM). Evolution of a pre-malignant cell into a malignant cell, as well as further tumor progression, dissemination, and relapse, require development of multiple driver lesions conferring selective advantage of the dominant clone and allowing subsequent evolution under selective pressure of microenvironment and treatment. This process of natural selection facilitates tumor plasticity leading to the formation of genetically complex and heterogenous tumors that are notoriously difficult to treat. Better understanding of the mechanisms underlying tumor evolution in MM and identification of lesions driving the evolution from the premalignant clone is therefore a key to development of effective treatment and long-term disease control. Here, we review recent advances in clonal evolution patterns and genomic landscape dynamics of MM, focusing on their clinical implications.

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“…Novel experimental methodologies may enable us to overcome the remaining issues shown here. In fact, the single-cell technique made detailed characterization of cells and their microenvironment, and to answer questions that could not be addressed by the conventional technique ( 143 ). In the context of acute GVHD, scRNA-seq has identified a novel regulator of T cell alloimmunity ( 144 ).…”

Section: Emerging Problems and Future Perspectivesmentioning

confidence: 99%

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

Ikegawa

Matsuoka

2021

Front. Immunol.

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CD4+CD25+Foxp3+ regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.

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Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing

Cited by 166 publications

References 52 publications

S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma

Clonal Evolution of Multiple Myeloma—Clinical and Diagnostic Implications

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

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