Search

We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a "static progression model", where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a "spontaneous evolution model", where a change in the subclonal composition is observed. We also observe that activation-induced cytidine deaminase plays a major role in shaping the mutational landscape of early subclinical phases, while progression is driven by APOBEC cytidine deaminases. These results provide a unique insight into myelomagenesis with potential implications for the definition of smoldering disease and timing of treatment initiation. [ABSTRACT FROM AUTHOR]

Alternative cleavage and polyadenylation (ApA) is known to alter untranslated region (3ʹUTR) length but can also recognize intronic polyadenylation (IpA) signals to generate transcripts that lose part or all of the coding region. We analyzed 46 3ʹ-seq and RNA-seq profiles from normal human tissues, primary immune cells, and multiple myeloma (MM) samples and created an atlas of 4927 high-confidence IpA events represented in these cell types. IpA isoforms are widely expressed in immune cells, differentially used during B-cell development or in different cellular environments, and can generate truncated proteins lacking C-terminal functional domains. This can mimic ectodomain shedding through loss of transmembrane domains or alter the binding specificity of proteins with DNA-binding or protein–protein interaction domains. MM cells display a striking loss of IpA isoforms expressed in plasma cells, associated with shorter progression-free survival and impacting key genes in MM biology and response to lenalidomide. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a malignancy of plasma cells within the bone marrow characterized by bone loss, renal disease, and immunodeficiency. Recent advances in the understanding of MM pathogenesis have improved established conventional cytotoxic therapy as well as transplantation regimens. Despite these advances, median overall survival is only 3–5 years. Therefore new therapies are urgently needed. Besides thalidomide, whose antimyeloma activity has only recently been defined, a plethora of novel agents, including the thalidomide-derived immunomodulatory drugs and bortezomib, have been identified to directly target the tumor cell or its microenvironment, and thereby inhibit MM cell growth and survival, and to overcome drug resistance. After validation of their preclinical anti-MM activity, several clinical trials are now ongoing to test the efficacy of these novel therapeutics, administered alone or in combination with conventional or other novel therapeutics and bone marrow transplantation. This article reviews the development of MM therapy, from its initial description approximately 150 years ago to the novel therapy regimens of recent years, highlighting that MM may soon become a chronic disease. [ABSTRACT FROM AUTHOR]

Presents an immunofluoresence microscopy image of neural progenitor cells expressing tyrosine hydroxylase. Result of straining cells β-tubulin (green), tyrosine hydroxylase (red) and green fibrillary acidic protein (GFAP; blue); Microscope through which the image was acquired; Measurement of scale bar.