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Familial Multiple Myeloma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
IgH translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 (IgH translocated multiple myeloma) are found in 30% of cases, and are due to errors of IgH switch recombination and somatic hypermutation resulting in the juxtaposition of IgH gene sequences located at chromosome 14q32 with non-immunoglobulin DNA loci of 11q13, 4p16.3, 16q23, 20q11, and 6p21. Specifically, t(11;14)(q13;q32) leads to the dysregulation of CCND1 (cyclin D1, which is responsible for 15% of cases); t(4;14)(p16;q32) puts oncogenes FGFR3 and MMSET under control of the IgH gene locus and increases the expression of cyclin D2 (6% of cases); t(14;16)(q32;q23) and t(14;20)(q32;q11) also bring oncogenes C-MAF and MAFB within the IgH gene locus and enhance cyclin D2 expression (representing 4% and <1% of cases, respectively), and t(6;14)(p21;q32) as well as other IgH translocations contributes to the increased expression of CCND3 (cyclin D3, 5% of cases) [1,2].
Can we accelerate the osteoporotic bone fracture healing response?
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Martijn van Griensven, Elizabeth Rosado Balmayor
In a preliminary in vitro study for bone regeneration in an osteoporotic setting, we could show that transfecting osteoporotic osteoblasts using lipofectamine and antagomir for miR-100 was able to restore the transcription of BMP-R2. Thereby, osteoanabolic signals could be transferred again into the osteoblasts that started to produce collagen Iα1 as a typical protein of the bone extracellular matrix. Moreover, the osteoblasts increase the production of alkaline phosphatase and osteocalcin. Using an antagomir against miR-148a increased MAFB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B) and thereby inhibited the maturation of osteoclasts. This resulted in less resorptive activity.
Plasma Cell Neoplasms
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The majority of patients with MGUS have chromosomal abnormalities, most of them involving IGH gene on chromosome 14q32 [9,131,138]. The most common partner genes include CCND1 (11q13), FGFR3/MMSET (4p16.3), CCND3 (6p21), c-MAF (16q23), and MAFB (20q11) [68,69,78,138]. The t(11;14) is present in 15%–25%, t(4;14) in 2%–9%, and t(14;16) in 1%–5%. Approximately 40% of MGUS is associated with hyperdiploidy, usually of the odd number of chromosomes (except 13) [17,30,138,139]. The most common single chromosome abnormalities detected in MGUS were gains of chromosomes 9 (23%) and/or 6 (21%) and losses of chromosomes 13 (21%) and/or 17 (17%) [140]. Compared with myeloma, MGUS patients were found to have both a lower incidence of gains of chromosome 9 (23% vs. 54%) and monosomy 13/del(13q) (21% vs. 38%). One of the few differential genetic lesions between myeloma and MGUS is the presence of RAS mutations in myeloma [9]. Rasmussen et al. [109] suggested that RAS mutations provided a genetic marker if not a causal event in the evolution of MGUS to PCM.
Deep sequencing as an approach to understanding the complexity and improving the treatment of multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Louis S. Williams, Jessica Caro, Beatrice Razzo, Eileen M. Boyle, Gareth J. Morgan
The emergence of whole-genome sequencing allowed for accurate characterization signatures or ‘mutographs’ that reflects the mutational mechanisms underlying a particular event [58]. In order to better define mutational signatures in multiple myeloma, a landmark study in NDMM combined NGS with a non-negative matrix factorization algorithm to evaluate mutational signatures [37]. This investigation placed particular emphasis on MYC translocations and translocations involving the IGH locus for which there was adequate sequence information to define signatures [59]. This process identified a particular signature related to the apolipoprotein B editing complex (APOBEC) family of proteins. The signature, which is defined by C > T, C > G, and C > A substitutions in a TpC context, was enriched in patients harboring t(14;16) and t(14;20). These translocations overexpress MAF and MAFB, which are thought to regulate expression of the APOBEC proteins [60]. Kategis, a phenomenon associated with localized somatic hypermutation, was found to involve regions flanking translocations involving MYC and IGH loci [52,59,61]. This pattern has been attributed to the aberrant functioning of an adenosine deaminase (AID) that normally facilitates affinity maturation of germinal center B-cells [62].
Alzheimer’s disease: microglia targets and their modulation to promote amyloid phagocytosis and mitigate neuroinflammation
Published in Expert Opinion on Therapeutic Targets, 2020
It is important to note that, transformation of microglia to this ‘reactive’ fine-tuned state requires tight control through checkpoint mechanisms drafted to halt exaggerated inflammatory responses and tissue damage including direct inhibitory interactions of microglia with neurons through CD47, which transmits a ‘do not eat me’ signal to the microglia via CD172a/SIRPα or other ligand-receptor as CX3CL1-CX3CR1 and/or CD200-CD200R [43,44]. Soluble anti–inflammatory factors such as transforming growth factor-β (TGF-β), IL-10 and IL-4 also regulate inflammatory microglia-associated responses in the CNS, and further ‘self’-regulating mechanisms, such as those involving the transcription factor MafB have also been discovered [45]. However, under prolonged situations ranging from neurodevelopmental disorders, traumatic injuries, infectious diseases, and psychiatric disorders, to tumors, when a reparative microglial activity is necessary, dysregulation of these mechanisms can play a crucial role in driving both neurodegenerative and neuroinflammatory events [46]. It has recently become clear that microglia are involved in many, if not all CNS diseases. Although microglia are included in the vast majority of neurodegenerative disorders, the mechanisms for their activation and possible contributions to neuronal degeneration remain an intense topic of debate [47].
Regenerating β cells of the pancreas – potential developments in diabetes treatment
Published in Expert Opinion on Biological Therapy, 2018
Islet cell lineage is further specified by expression of other transcription factors such as NeuroD1, Nkx2.2, and Pax6 – genetic deletion of these proteins results in small disorganized islets and decreased numbers of all endocrine lineages [10,12,27–29]. The endocrine cells eventually differentiate into different islet cell types by expressing cell-type-specific transcription factors. For instance, expression of Arx leads to the formation of glucagon-producing α cells and expression of Pax4 triggers the differentiation of β cells, whereas loss of both Arx and Pax4 promotes the formation of somatostatin-producing δ cells [30,31]. Differentiation of β cells is also coupled with a loss of MafB expression and induction of MafA expression [32]. The mature β cells express several key transcription factors including MafA, Nkx2.2, Nkx6.1, Pax6, and Pdx1, all of which are essential for maintaining β-cell identity and function [18,32–35].