The non-coding RNA landscape of plasma cell dyscrasias

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel mechanisms of gene expression regulation often malfunctioning in cancer. Increasing evidence indicates that such non-coding molecules also feature in the pathobiology of PC dyscrasias, where they are endowed with strong therapeutic and/or prognostic potential. In this review, we aim to summarize the most relevant findings on the biological and clinical features of the non-coding RNA landscape of malignant PCs, with major focus on multiple myeloma. The most relevant classes of non-coding RNAs will be examined, along with the mechanisms accounting for their dysregulation and the recent strategies used for their targeting in PC dyscrasias. It is hoped these insights may lead to clinical applications of non-coding RNA molecules as biomarkers or therapeutic targets/agents in the near future

Ex vivo propagation in a novel 3D high-throughput co-culture system for multiple myeloma

PURPOSE: Multiple myeloma (MM) remains an incurable hematologic malignancy which ultimately develops drug resistance and evades treatment. Despite substantial therapeutic advances over the past years, the clinical failure rate of preclinically promising anti-MM drugs remains substantial. More realistic in vitro models are thus required to better predict clinical efficacy of a preclinically active compound. METHODS: Here, we report on the establishment of a conical agarose 3D co-culture platform for the preclinical propagation of primary MM cells ex vivo. Cell growth was compared to yet established 2D and liquid overlay systems. MM cell lines (MMCL: RPMI-8226, U266, OPM-2) and primary patient specimens were tested. Drug sensitivity was examined by exploring the cytotoxic effect of bortezomib and the deubiquitinase inhibitor auranofin under various conditions. RESULTS: In contrast to 2D and liquid overlay, cell proliferation in the 3D array followed a sigmoidal curve characterized by an initial growth delay but more durable proliferation of MMCL over 12 days of culture. Primary MM specimens did not expand in ex vivo monoculture, but required co-culture support by a human stromal cell line (HS-5, MSP-1). HS-5 induced a \u3e fivefold increase in cluster volume and maintained long-term viability of primary MM cells for up to 21 days. Bortezomib and auranofin induced less cytotoxicity under 3D vs. 2D condition and in co- vs. monoculture, respectively. CONCLUSIONS: This study introduces a novel model that is capable of long-term propagation and drug testing of primary MM specimens ex vivo overcoming some of the pitfalls of currently available in vitro models

Proceedings from the BMT CTN Myeloma Intergroup Workshop on Immune and Cellular Therapy in Multiple Myeloma.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup conducted a workshop on Immune and Cellular Therapy in Multiple Myeloma on January 7, 2022. This workshop included presentations by basic, translational and clinical researchers with expertise in plasma cell dyscrasias. Four main topics were discussed: 1) platforms for myeloma disease evaluation; 2) insights into pathophysiology; 3) therapeutic target and resistance mechanisms; and 4) cellular therapy for multiple myeloma. In the present report, we provide a comprehensive summary of these workshop presentations

Integrin β7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion

Integrin-β7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with MAF gene activation. Although the involvement of several integrin family members in MM-stoma cell interaction is well documented, the specific biologic functions regulated by integrin-β7 in MM are largely unknown. Clinically, we have correlated integrin-β7 expression in MM with poor survival outcomes post autologous stem cell transplantation and postsalvage therapy with bortezomib. Functionally, we have found that shRNA-mediated silencing of ITGB7 reduces MM-cell adhesion to extra-cellular matrix elements (fibronectin, E-cadherin) and reverses cell-adhesion–mediated drug resistance (CAM-DR) sensitizing them to bortezomib and melphalan. In addition, ITGB7 silencing abrogated MM-cell transwell migration in response to SDF1α gradients, reduced vessel density in xenografted tumors, and altered MM cells in vivo homing into the BM. Mechanistically, ITGB7 knockdown inhibited focal adhesion kinase (FAK) and Src phosphorylation, Rac1 activation, and SUMOylation, reduced VEGF production in MM–BM stem cell cocultures and attenuated p65-NF-κB activity. Our findings support a role for integrin-β7 in MM-cell adhesion, migration, and BM homing, and pave the way for a novel therapeutic approach targeting this molecule