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Precision medicine in acute myeloid leukemia
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Mutations of the spliceosome machinery range from <1% to 90% in secondary AML compared to <1% to 10.5% in de novo AML (Mohamed et al., 2014; Saez et al., 2017; Yoshida et al., 2011). Mutations in splicing factor 3 subunit b1 (SF3b1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), serine arginine-rich splicing factor 2 (SRSF2), and U2 small nuclear RNA auxiliary factor with zinc finger CCCH-type (ZRSR2) occur in AML. A number of natural products derived from distinct species of bacteria have been found to target the SF3B component of the spliceosome and demonstrate potent antitumor activities. One of the first to be identified was FR901464, a fermentation product from Pseudomonas, which has been used as a structural model for the synthesis of several stable chemical analogs of similar or greater potency. In particular, meayamycin B, a soluble synthetic derivative, demonstrates important potential for development as a novel therapy for AML treatment (Wojtuszkiewicz et al., 2014). Meayamycin B inhibits the SF3B1 subunit and can shift alternative splicing of MCL-1 to promote expression of the proapoptotic MCL-1s isoform. Although SF3B1 is among the most commonly mutated splice factors both in MDS and AML, these mutations are not located in the putative binding region of spliceosome inhibitors like meayamycin B, suggesting that they could be effective therapeutic options for patients with these mutations (de Necochea-Campion et al., 2016). Further inhibitors (17S-FD-895, pladienolide B, and sudemycins) were also tried (Shirai et al., 2017; Zhou and Chng 2017).
Molecular Biology of the Amelogenin Gene
Published in Colin Robinson, Jennifer Kirkham, Roger Shore, Dental Enamel, 2017
James P. Simmer, Malcolm L. Snead
The primary amelogenin transcripts are processed along multiple splicing pathways to yield an assortment of mRNAs. In mouse the percentage of transcripts passing through a particular splicing pathway changes during odontogenesis.57 Using RT-PCR of RNA isolated from the enamel organ epithelia of mouse molars for embryonic days 14 through 19 (El4 through El9), it was demonstrated that initially only the mRNA encoding the Ml80 amelogenin isoform is synthesized. At E16 the mRNA encoding the Ml56 isoform appears. As each primary RNA transcript is initially identical, changes in the splicing pattern suggests the presence of a trans-acting splicing factor that affects splice site selection and, therefore, a posttranscriptional mechanism that can regulate the specific amelogenin isoforms secreted into the enamel extracellular matrix. Induction of specific splicing factors has been observed following stimulation by signalling molecules. Altered splice site selection of mRNAs for other (nonenamel matrix) proteins has been found in response to TGF,58 interleukin 1,59 12-O-tetradecanoylphorbol-13-acetate (TPA),60 DMSO and retinoic acid,61 and 1,25-dihydroxyvitamin D.57 Changes in the splicing pattern of the src pre-mRNA follows protein kinase C stimulation in the absence of protein synthesis, suggesting that resident splicing factors could be activated or inactivated (possibly by phosphorylation) and rapidly respond to external signals.60
Genetic Testing of Y-Chromosome Microdeletion
Published in Nicolás Garrido, Rocio Rivera, A Practical Guide to Sperm Analysis, 2017
Jason C. Chandrapal, James M. Hotaling
AZFb is the largest of the three spanning 6.2 Mb, extending from palindrome 5 to the proximal portion of palindrome 1 (P5/proximal-P1) (Figure 5.6). Deletion patterns within this region can range from deletion of the AZFb or just parts, including flanking regions. The main gene in this region is RBMY1, a testis-specific splicing factor. RBMY1 was one of the first AZF candidate genes to be described.38 RBMY1 belongs to the RBMY gene family, a family of 20–50 testis-specific genes and pseudogenes spread over both arms of the Y chromosome.39 Within this family, RBMY1 is the only one that is actively transcribed and is concentrated within the AZFb region.40 Deletion of the RBMY mouse homolog, Rbm, results in infertility.41 The exact function of RBMY1 in human spermatogenesis is unclear, other than it is a nuclear protein involved in spermatogenetic pre-mRNA splicing.42 Taken together the testis specificity, AZFb location, and lack of gene expression in YCMD make RBMY1 an ideal AZF gene candidate. Deletion occurs in 1%–5% of cases and causes maturation arrest at the primary spermatocyte stage (Table 5.3). The suspension of the spermatocytes in a premeiotic, polyploidy state restricts their use in assisted reproduction and therefore TESE is not recommended.
Identifying prognostic gene panels in acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Joaquin Sanchez-Garcia, Josefina Serrano, Esther Prados de La Torre, Juana Serrano-López, Clara Aparicio-Perez, E Barragán, Pau Montesinos
In the pivotal work of Lindsley et al [94], the presence of in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Importantly, in a majority of patients with s-AML achieving morphological remission, these driver mutations are still detectable, reinforcing the hypothesis that these cases may have had an unrecognized period of antecedent myelodysplasia before AML diagnosis. These eight genes act as splicing factor and chromatin-modifiers and are globally mutated in 13–15% of AML cases. SRSF2, SF3B1, U2AF1, and ZRSR2 are splicing factor (SF) genes encoding for components of spliceosomes which are nuclear structures composed of five small nuclear RNAs (snRNA) and approximately 150 proteins, which catalyze the splicing reaction [95]. Mutations in SF genes are very frequent in different MDS subtypes (45–85%), being mutations in SF3B1 associated mostly in MDS with ring-sideroblasts determining a new-entity with better prognosis than other SF mutations [96,97]. Notwithstanding the differential impact on outcomes of different SF mutations in AML is less clear [98] and SF mutations can be consistently associated with other genetic categories such as MECOM-rearranged AML [99,100].
Peripheral vascular disease: preclinical models and emerging therapeutic targeting of the vascular endothelial growth factor ligand-receptor system
Published in Expert Opinion on Therapeutic Targets, 2021
Vijay Chaitanya Ganta, Brian H. Annex
While progress has been made in understanding the pathological consequences of VEGF165b expression in ischemic muscle, the upstream processes that regulate VEGF165b production is still in their infancy. For example, the splicing machinery that regulates VEGF165b seems to be cell/tissue-specific [49,125–128] and it is yet to be seen what regulates the preferential production of VEGF165b in endothelial cells in non-ischemic and ischemic tissue. In general, splice factors control target and process multiple genes, rendering it difficult to target a splicing factor to achieve therapeutic benefit. However, identifying a 3ʹ specific slice factor regulated by ischemia might provide a way to target VEGF165b upstream. This is an important aspect to consider due to the loss of VEGFR2 signaling upon VEGF165b inhibition. Even though VEGF165b inhibition enhanced perfusion despite decreased VEGFR2 activation in preclinical models [48], human pathology is more complex to simply overlook the possibility of VEGFR2 signaling inhibition. Hence, more studies are needed to understand the upstream mechanism of preferential VEGF165b production in ischemic tissues.
Unpacking the genetic etiology of uveal melanoma
Published in Expert Review of Ophthalmology, 2020
Sophie Thornton, Helen Kalirai, Karen Aughton, Sarah E. Coupland
The TCGA-UM study was the first to identify change-of-function mutations in ‘Serine and Arginine Rich Splicing Factor 2ʹ SRSF2, with a proclivity for in-frame deletions in 4% of UM [39]. Tumors with SRSF2 mutations lacked either SF3B1 or EIF1AX mutations, with each subset having unique methylation profiles [39]. When analyzed alongside RNA-seq data for the corresponding sample, the in-frame deletions of SRSF2 altered translation initiation, skipping exons in EIF4A2 and FYN [39]. In a separate study investigating the prevalence of SRSF2 mutations in SF3B1 wild-type UM, heterozygous in-frame SRSF2 deletions affecting amino acids 92–100 were detected in two UM [94], and again were mutually exclusive to BAP1, SF3B1, and EIF1AX mutations [94]. These mutations are thought to play a crucial role in tumorigenesis by mis-splicing that affects elongation initiation factors and signaling gene transcripts [95]. Additionally, mutations in the splicing factor SRSF2 resulting in a change-of-function have also been identified in two separate studies in the same region reported to disrupt splicing in myelodysplastic syndrome [96,97].