High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

Solimando, Antonio Giovanni; Viá, Matteo Da; Cicco, Sebastiano; Leone, Patrizia; Lernia, Giuseppe Di; Giannico, Donato; Desantis, Vanessa; Frassanito, Maria Antonia; Morizio, Arcangelo; Tascon, Julia Delgado; Melaccio, Assunta; Saltarella, Ilaria; Ranieri, G.; Ria, Roberto; Rasche, Leo; Kortüm, K. Martin; Beilhack, Andreas; Racanelli, Vito; Einsele, Hermann

doi:10.3390/jcm8070997

Cited by 53 publications

(51 citation statements)

References 195 publications

(277 reference statements)

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“…In the frame of this thinking, an altered basal autophagy process could occur in myeloma PCs because of the many genetic alterations, also in a tumor microenvironment driven fashion. [54].…”

Section: Discussionmentioning

confidence: 99%

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Lernia

Leone

Solimando

et al. 2020

JCM

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Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.

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Section: Discussionmentioning

confidence: 99%

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Lernia

Leone

Solimando

et al. 2020

JCM

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“…However, it is tempting to speculate that partial loss of BLIMP1 activity could alter the transcriptional landscape of cancer cells impacting the differentiation state and expression of cell cycle genes such as MYC (Montes-Moreno et al, 2017; Shaffer et al, 2008). Interestingly, BLIMP1 genetic aberrations associate with poor prognosis in MM (Solimando et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

Barbosa

D’Andrea

et al. 2020

Preprint

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Highlights 28 • NF-kB and MYC co-activation originates (pre)plasmablast-like cancer 29 • NF-kB/MYC + renders cancer cells addicted to IL6 for survival and phenotypic stability 30 • NF-kB/MYC + cancers are alike a fraction of human plasmablastic lymphoma 31 • t(8;14)[MYC-IGH] multiple myeloma is linked to a NF-kB/MYC co-activation signature 32 33 2 Summary 34 NF-kB and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-kB is 35 necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus 36 unclear if NF-kB/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts 37 cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace 38 cell lineage and oncogene activation we found that NF-kB/MYC co-deregulation originated cancers with a 39 plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-40 IGH] multiple myeloma. Notably, in contrast to NF-kB or MYC activation alone, co-deregulation rendered 41 cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven 42 differentiation pressures can be accommodated at a cost in poorly-differentiated cancers. 43 44 Significance 45 Our studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of 46 NF-kB and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse 47 system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of 48 care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. 49 Notably, we found that NF-kB and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, 50 providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound 51 mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple 52 myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat 53 diseases. 54 55 Keywords 56 NF-kB, MYC, IL6, B-cell, plasma-cell, plasmablast, B-cell terminal differentiation, Diffuse large B-cell 57 lymphoma, plasmablastic lymphoma, multiple myeloma, phenotypic stability 58 59 60 61 62 63 64 65 66 67 90 Tornatore et al., 2014). 91 92 The knowledge that NF-kB directly induces the expression of genes essential in B-to-plasma cell 93 differentiation and that ABC-DLBCL cancer cells despite being mature B-cells display features of 94 plasmacytic differentiation suggest that a block of B-to-plasma cell is required in the pathogenesis of ABC-95 DLBCL. Consistently, the activity of BLIMP1, key for B-to-plasma cell differentiation, is lost exclusively 96 in DLBCL of the ABC subtype through BLIMP1 genetic aberrations (∼30% of cases), and indirectly by 97 deregulated BCL6 expression from chromosomal translocations (∼26% of cases) (Mandelbaum et al.,98 2010; Pasqualuc...

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“…However, it is uncertain whether expressed syndecans have a critical role in tumor progression participants or are bystanders. Moreover, syndecan-1 activation has been correlated to tumor development and malignancy in myeloma [183,184]. In research regarding a mammalian carcinogenesis model of the mouse, it was elucidated that syndecan-1 is necessary for Wnt1 to promote tumor formation [185], which seems to be associated with β-catenin/TCF signaling [185].…”

Section: Syndecans and Cancermentioning

confidence: 99%

Oncogenic Signaling Pathways in Cancer: An Overview

Derakhshani¹,

Rostami²,

Taefehshokr³

et al. 2020

Preprint

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Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

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High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

Cited by 53 publications

References 195 publications

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

Oncogenic Signaling Pathways in Cancer: An Overview

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