Myeloma genomics

UNLABELLED: The histone H3K27 demethylase KDM6A is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling. Most importantly, KDM6A binds and activates NLRC5 and CIITA encoding regulators of Major Histocompatibility Complex (MHC) genes. Patient data indicate that NLRC5 and CIITA, are downregulated in MM with low KDM6A expression...

Infection is the leading cause of morbidity and mortality in patients with multiple myeloma (MM). Studying the relationship between different traits of Coronavirus 2019 (COVID-19) and MM is critical for the management and treatment of MM patients with COVID-19. But all the studies on the relationship so far were observational and the results were also contradictory. Using the latest publicly available COVID-19 genome-wide association studies (GWAS) data, we performed a bidirectional Mendelian randomization (MR) analysis of the causality between MM and different traits of COVID-19 (SARS-CoV-2 infection, COVID-19 hospitalization, and severe COVID-19) and use multi-trait analysis of GWAS(MTAG) to identify new associated SNPs in MM...

The complexity of Multiple Myeloma (MM) is driven by several genomic aberrations, interacting with disease-related and/or -unrelated factors and conditioning patients' clinical outcome. Patient's prognosis is hardly predictable, as commonly employed MM risk models do not precisely partition high- from low-risk patients, preventing the reliable recognition of early relapsing/refractory patients. By a dimensionality reduction approach, here we dissect the genomic landscape of a large cohort of newly diagnosed MM patients, modelling all the possible interactions between any MM chromosomal alterations...

Multiple myeloma (MM) is a heterogeneous disease with survival ranging from months to decades. The goal of 'cure' remains elusive for most patients, but has been shown to be possible, with durable remission and a transition to a plateau phase (analogous to monoclonal gammopathy of uncertain significance/smoldering Myeloma (MGUS/SMM)). Two representative cases set the stage to illustrate how this might be possible and what still needs to be determined to achieve functional disease control over a prolonged period...

Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC...

With the advent of outperforming and massive laboratory tools, such as multiparameter flow cytometry and next-generation sequencing, hematopoietic cell clones with putative abnormalities for a variety of blood malignancies have been appreciated in otherwise healthy individuals. These conditions do not fulfill the criteria of their presumed cancer counterparts, and thus have been recognized as their precursor states. This is the case of monoclonal gammopathy of unknown significance (MGUS), the first blood premalignancy state described, preceding multiple myeloma (MM) or Waldenström macroglobulinemia (WM)...

Allogeneic chimeric antigen receptor (CAR) T-cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR T cells. Key considerations in the development of allogeneic CAR T-cell therapies include prevention of GvHD and suppression of allograft rejection. Here we describe preclinical data supporting the ongoing first-in-human clinical study, the CaMMouflage trial (NCT05722418), evaluating CB-011 in patients with relapsed/refractory multiple myeloma. CB-011 is a hypoimmunogenic, allogeneic anti-B cell maturation antigen (BCMA) CAR T-cell therapy candidate...

OBJECTIVES: Multiple myeloma (MM) is a plasma cell malignancy characterized by a monoclonal expansion of plasma cells that secrete a characteristic M-protein. This M-protein is crucial for diagnosis and monitoring of MM in the blood of patients. Recent evidence has emerged suggesting that N-glycosylation of the M-protein variable (Fab) region contributes to M-protein pathogenicity, and that it is a risk factor for disease progression of plasma cell disorders. Current methodologies lack the specificity to provide a site-specific glycoprofile of the Fab regions of M-proteins...

BACKGROUND: Multiple myeloma (MM) is an incurable B-cell malignancy, but with the emergence of immunotherapy, a potential cure is hopeful. The individualized interaction between the tumor and bone marrow (BM) microenvironment determines the response to immunotherapy. Angiogenesis is a constant hallmark of the BM microenvironment in MM. However, little is known about the potency ability of angiogenesis-associated genes (AAGs) to regulate the immune microenvironment of MM patients. METHODS: We comprehensively dissected the associations between angiogenesis and genomic landscapes, prognosis, and the immune microenvironment by integrating 36 AAGs...

AIMS: The aims of this study were to explore the molecular mechanism of mitophagy in multiple myeloma (MM) and to develop an effective prognostic signature for the disease based on mitophagy-related genes (MRGs). METHODS: Three gene sets from the Reactome database were used to explore MRGs, following which those that were differentially expressed between MM and normal samples were investigated using the data from the Genomic Data Commons-Multiple Myeloma Research Foundation-CoMMpass Study...

Chromotrypsis, a phenomenon resulting from catastrophic mitotic errors and genomic instability, is defined by the occurrence of multiple DNA double-strand breaks in one or more chromosomes, subsequently subject to error-prone repair mechanisms. This unique process results in extensive rearrangements in the affected chromosomes, leading to loss of tumor suppressor function, the creation of fusion genes and/or activation of oncogenes. The importance of chromothripsis in cancer, especially in the field of hematological disorders, underscores the intricate interplay between genomic instability and the genesis of alterations that contribute to cancer...

BACKGROUND: Multiple myeloma (MM) is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow. The translocation, (t)(4;14), results in high-risk MM with limited treatment alternatives. Thus, there is an urgent need for identification and validation of potential treatments for this MM subtype. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets...

During the last 20 years, proteasome inhibitors have been a cornerstone for the therapeutic management of multiple myeloma (MM). This review highlights how MM research has evolved over time in terms of our understanding of the mechanistic basis for the pronounced clinical activity of proteasome inhibitors in MM, compared with the limited clinical applications of this drug class outside the setting of plasma cell dyscrasias.

B/T mixed phenotype acute leukemia (MPAL) is a rare aggressive leukemia. Three cases of B/T MPAL were identified with comprehensive immunophenotypic, cytogenetic, and molecular studies. T-lineage predominant B/T MPAL shares a genetic signature with T-ALL whereas B/T lineage co-dominant B/T MPAL lacks such a T-ALL signature . All three patients were treated with lineage-matched-ALL therapy and alive at the last follow-up. Our study is the first to demonstrate molecular heterogeneity within B/T MPAL in a context of an immunophenotype of T-lineage versus B-lineage predominance...

This study delves into the intricate interaction between DNA and nanosystems, exploring its potential implications for biomedical applications. The focus lies in understanding the adsorption geometry of DNA when in proximity to plasmonic nanoparticles, utilizing ultrasensitive vibrational spectroscopy techniques. Employing a combined Raman-SERS analysis, we conducted an in-depth examination to clarify the molecular geometry of interactions between DNA and silver nanoparticles. Our findings also reveal distinctive spectral features regarding DNA samples due to their distinctive genome stability...

Multiple myeloma (MM) is a common type of blood cancer affecting plasma cells originating from the lymphoid B-cell lineage. It accounts for about 10% of all hematological malignancies and can cause significant end-organ damage. The emergence of genomic technologies such as next-generation sequencing and gene expression analysis has opened new possibilities for early detection of multiple myeloma and identification of personalized treatment options. However, there remain significant challenges to overcome in MM research, including integrating multi-omics data, achieving a comprehensive understanding of the disease, and developing targeted therapies and biomarkers...

Multiple myeloma is a plasma cell neoplasm driven by primary (e.g. hyperdiploidy; IGH translocations) and secondary (e.g. 1q21 gains/amplifications; del(17p); MYC translocations) chromosomal events. These are important to detect as they influence prognosis, therapeutic response and disease survival. Currently, cytogenetic testing is most commonly performed by interphase fluorescence in situ hybridisation (FISH) on aspirated bone marrow samples. A number of variations to FISH methodology are available, including prior plasma cell enrichment and incorporation of immunophenotypic plasma cell identification...

PURPOSE: Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS: To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS: Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications...

BACKGROUND: Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined. METHODS: We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance of MIC expression in MM...

BACKGROUND: Dengue virus infection is an intriguing illness. It is traditionally thought of as a self-limited and nonpersistent disease. OBJECTIVES: We report a case with persistent dengue virus genome detectable in hematopoietic cells of a person with remote infection. METHODS: A patient with multiple myeloma in remission was prepared for peripheral blood stem cell (PBSC) transplantation. Plasma and G-CSF-stimulated, mobilized PBSCs were collected...