No abstract

The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32). According to several studies, this translocation represents a unique subset of patients with relatively favorable outcomes. Using combined analyses of morphology and fluorescence in situ hybridization (I-FISH), we examined the co-occurrence rates of t(11;14) with seven chromosomal aberrations (CAs), del(13q), del(17p), del(1p), gain(1q), multiple gains(1q), del(16q), and del(IGH), and assessed the effect of the different combinations on patient outcomes, with overall survival (OS) as the main outcome measure. Bone marrow samples and clinical data from 212 patients with MM with t(11;14) were analyzed. At least two additional CAs were found in 35% (75/205) of patients and a strong correlation between specific CAs. The occurrence of three CAs [multiple gains of (1q) (HR = 6.94, P = 0.001), del(1p) (HR = 4.47, P = 0.008), and del(IGH) (HR = 2.38, P = 0.002)] exerted a profoundly deleterious effect on median OS when compared with patients with t(11;14) only. Del(17p) and del(13q) have also exerted a deleterious effect albeit to a lesser extent (HR = 2.05, P = 0.07 and HR = 1.81, P = 0.03, respectively). When compared with t(11;14) alone, the addition of certain CAs lead to worse outcomes. These findings may have important clinical and biological implications. Patients with coexisting adverse lesions and t(11;14) may be considered at high risk and managed accordingly. © 2016 Wiley Periodicals, Inc.

The three neurexins genes (NRXN1/2/3) encode polymorphic synaptic membrane proteins that are involved in cognitive functioning. Neurexins' selectivity of function is presumably conferred through differential use of 2 promoters and 5 alternative splicing sites (SS#1/2/3/4/5). In day-old rat brain neurons grown in culture, activation (depolarization) induces reversible, calcium dependent, repression of NRXN2α SS#3 insert. The effects of depolarization on NRXN1/2/3α splicing and biochemical pathways mediating them were further studied in these neurons. NRXN1/2/3α splicing in the course of memory formation in vivo was also explored, using fear conditioning paradigm in rats in which the animals were trained to associate an aversive stimulus (electrical shock) with a neutral context (a tone), resulting in the expression of fear responses to the neutral context.In the cultured neurons depolarization induced, beside NRXN2α SS#3, repression of SS#3 and SS#4 exons in NRXN3α but not NRXN1α. The repressions were mediated by the calcium/protein kinase C/Rho-associated protein kinase (ROCK) pathway. Fear conditioning induced significant and transient repressions of the NRXN1/2/3α SS#4 exons in the rat hippocampus. ROCK inhibition prior to training attenuated the behavioral fear response, the NRXN1/2/3α splicing repressions and subsequent recovery and the levels of excitatory (PSD95) and inhibitory (gephyrin) synaptic proteins in the hippocampus. No such effects were observed in the prefrontal cortex. Significant correlations existed between the fear response and hippocampal NRXN3α and NRXN2α SS#4 inserts as well as PSD95 protein levels. Hippocampal NRXN1α SS#4 insert and gephyrin levels did not correlate with the behavioral response but were negatively correlated with each other.These results show for the first time dynamic, experience related changes in NRXN1/2/3α alternative splicing in the rat brain and a role for ROCK in them. Specific neurexins' transcripts may be involved in synaptic remodeling occurring at an intermediate (hours) time scale in the course of memory formation.