In mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases, while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism ensuring the silencing of one X in females, may participate in these sex biases. We perturbed the expression of the trigger of XCI, the noncoding RNA Xist , in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signaling pathway, in monocyte/macrophages and dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti–nucleic acid autoantibodies, increased frequencies of age-associated and germinal center B cells, and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signaling is dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity.

Multiple myeloma (MM) is a currently incurable malignancy of antibody-secreting plasma cells in the bone marrow. Taken together with its premalignant precursor stage disease (monoclonal gammopathy of undetermined significance), MM accounts for ~20% of all hematological malignancies, making it one of the most common blood cancers. One of the prominent features of MM is a high level of genetic and biological diversity, which underlies the significant heterogeneity in the rates of disease progression observed between patients. For more than a decade, short- and more recently long noncoding RNAs (ncRNAs) have been investigated in tumor plasma cells of MM patients to understand the contribution of these molecules to disease progression, treatment response, and prognosis. In this chapter, we describe the existing databases documenting the changes in ncRNA expression in MM, highlight important ncRNAs for whom the role in the disease has been characterized, and also describe the complex interactions between ncRNAs and the major signaling pathways involved in this disease. Finally, we discuss the use of ncRNAs as potential diagnostic and prognostic biomarkers for MM, as well as recent efforts to target ncRNAs that could eventually complement existing therapies to achieve durable relapse and eventual cure.

Over the past 15 years, long non-coding RNAs (lncRNA) have emerged as an important class of regulatory molecules. The currently accepted definition is that lncRNA refers to RNA molecules with little or no protein-coding potential, and which are greater than 200 nucleotides in length, a size cut-off chosen largely to distinguish them from the more-extensively characterised group of small non-coding regulatory RNAs, which includes micro (mi)RNAs, small inhibitory (si)RNAs and PIWI-interacting (pi)RNAs [1]. A recent compilation of annotations from diverse sources identified nearly 57,000 genes encoding lncRNAs in the human genome [2].

Multiple myeloma (MM) is a currently incurable malignancy of antibody-secreting plasma cells. Long non-coding RNAs (lncRNAs) have been recognised as an important class of regulatory molecules which are increasingly implicated in tumorigenesis. While recent studies have demonstrated changes in expression of lncRNAs in MM, the functional significance and molecular pathways downstream of these changes remain poorly characterised. In this study, we have performed CRISPR-mediated deletion of the locus encoding the lncRNA Colorectal Neoplasia Differentially Expressed (CRNDE), a known oncogenic lncRNA that is overexpressed in plasma cells of MM patients and is a marker of poor prognosis. We found that CRISPR-mediated deletion of the CRNDE locus in MM cells decreases proliferation and adhesion properties, increases sensitivity to Dexamethasone and reduces tumour growth in an in vivo xenograft model. Transcriptomic profiling in CRNDE-deleted MM cells demonstrated that CRNDE activates expression of a number of genes previously implicated in the aetiology of MM, including IL6R. We further demonstrate that deletion of the CRNDE locus diminishes IL6 signalling and proliferative responses in MM cells. Altogether this study reveals the IL6 signalling pathway as a novel mechanism by which CRNDE impacts upon MM cell growth and disease progression.

Multiple myeloma (MM) is a malignancy of antibody-secreting plasma cells which remains incurable, despite significant improvements in treatment and patient care. MM is characterized by a wide clinical and prognostic spectrum, even within groups bearing the same primary initiating cytogenetic event, for which the molecular mechanisms responsible remain poorly understood. Long non-coding RNAs (lncRNAs; broadly defined as non-coding RNAs of > 200 nt) have recently emerged as an important class of regulatory molecules, exercising diverse functions in normal cells and tissues, and are increasingly implicated in tumorigenesis and cancer progression. However at present the contribution of lncRNAs to the progression and clinical variability of MM is largely unknown.