Actionable Strategies to Target Multiple Myeloma Plasma Cell Resistance/Resilience to Stress: Insights From “Omics” Research

Abstract

While the modern therapeutic armamentarium to treat multiple myeloma (MM) patients allows a longer control of the disease, this second-most-frequent hematologic cancer is still uncurable in the vast majority of cases. Since MM plasma cells are subjected to various types of chronic cellular stress and the integrity of specific stress-coping pathways is essential to ensure MM cell survival, not surprisingly the most efficacious anti-MM therapy are those that make use of proteasome inhibitors and/or immunomodulatory drugs, which target the biochemical mechanisms of stress management. Based on this notion, the recently realized discoveries on MM pathobiology through high-throughput techniques (genomic, transcriptomic, and other "omics"), in order for them to be clinically useful, should be elaborated to identify novel vulnerabilities in this disease. This groundwork of information will likely allow the design of novel therapies against targetable molecules/pathways, in an unprecedented opportunity to change the management of MM according to the principle of "precision medicine." In this review, we will discuss some examples of therapeutically actionable molecules and pathways related to the regulation of cellular fitness and stress resistance in MM.

Identification of TFG- and Autophagy-Regulated Proteins and Glycerophospholipids in B Cells

“…17,18 Autophagy also cooperates with the ubiquitin proteasome system (UPS) and ER-associated degradation (ERAD) in controlling survival of normal and malignant plasma cells. 19 In a proteomic screen for interaction partners of CARD11, we identified a 50 kDa protein named TRK-fused gene (TFG) in the mouse B lymphoma line CH27. 20 TFG consists of 397 amino acids structured into an N-terminal PB1 protein−protein interaction domain, 21 a coiled-coil oligomerization domain, and a C-terminal proline-rich region.…”

“…The autophagy vesicle matures by lipidation of an ATG protein (Atg8 in yeast, LC3 and GABARAP subfamilies in mammals), which is required for autophagy vesicle expansion and closure. Germinal center B cells apply noncanonical autophagy to ensure mitochondrial homeostasis, while plasma cells rely on atg5 -dependent autophagy for sustainable antibody production and survival. , Autophagy also cooperates with the ubiquitin proteasome system (UPS) and ER-associated degradation (ERAD) in controlling survival of normal and malignant plasma cells …”

“… 17 , 18 Autophagy also cooperates with the ubiquitin proteasome system (UPS) and ER-associated degradation (ERAD) in controlling survival of normal and malignant plasma cells. 19 …”

Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma

“…2 Major efforts are being made to exploit targetable aberrations, which, together with high-throughput sequencing-based genomics, create the possibility of using personalized medicine strategies for the treatment of MM. 2,[18][19][20] Linked-read whole-genome sequencing (lrWGS) is a developing technology that allows for the creation of synthetic long reads from conventional short-read sequencing. Linked-read data are achieved by generating groups of reads or read clouds originating from a single high molecular weight (HMW) DNA molecule, which all carry a common barcode linking them together.…”

Quantitative proteomics and lipidomics of TFG-deficient B cells provide insights into mechanisms of autophagic flux and plasma cell biology

“…Plasma cells and germinal center B cells rely on autophagy (Martinez-Martin et al, 2017). In particular, autophagy cooperates with the ubiquitin-proteasome system (UPS), and ER-associated degradation (ERAD) in controlling survival of normal and malignant plasma cells (Manni et al, 2020).…”