Clinical implication and prognostic significance of FLT3-ITD and ASXL1 mutations in Egyptian AML patients: A singlecenter study

BACKGROUND: Both of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and Additional Sex Comb-like 1 (ASXL1) mutations are frequent and early genetic alteration events in acute myeloid leukemia (AML) patients. These genetic alterations may be associated with unfavorable prognosis. OBJECTIVE: Up to our knowledge, this is the first study performed to evaluate the clinical implication and prognostic significance of FLT3-ITD and ASXL1 mutations and their coexistence on the outcome of Egyptian AML patients. METHODS: Our study included 83 patients with AML who were subjected to immunophenotyping and detection of FLT3-ITD and ASXL1 gene mutation by polymerase chain reaction (PCR) and real-time PCR, respectively. RESULTS: FLT3-ITD and ASXL1 mutations were detected in 20.5% and 18.1% of AML patients respectively. Seven patients (8.4%) had co-expression of both genes’ mutation. FLT3-ITD mutation was significantly higher in younger age, higher WBCs count and poor cytogenetic risk patients (P= 0.01, < 0.001 and 0.008 respectively). ASXL1 mutation was significantly higher in intermediate cytogenetic risk patients (P= 0.2). The mean period of survival and relapse free survival (RFS) were significantly reduced in FLT3-ITD and ASXL1 mutations compared with their non-mutant types (P= 0.01 and 0.03 respectively). Both mutations were independent risk factors for overall survival (OS) and (RFS) in univariate and multivariate analysis in AML patients. CONCLUSION: FLT3-ITD and ASXL1 gene mutations or their coexistence can predict a poor prognosis in AML patients.

Role of the Forkhead Transcription Factors Fd4 and Fd5 During Drosophila Leg Development

Appendage development requires the coordinated function of signaling pathways and transcription factors to pattern the leg along the three main axes: the antero-posterior (AP), proximo-distal (PD), and dorso-ventral (DV). The Drosophila leg DV axis is organized by two morphogens, Decapentaplegic (Dpp), and Wingless (Wg), which direct dorsal and ventral cell fates, respectively. However, how these signals regulate the differential expression of its target genes is mostly unknown. In this work, we found that two members of the Drosophila forkhead family of transcription factors, Fd4 and Fd5 (also known as fd96Ca and fd96Cb), are identically expressed in the ventro-lateral domain of the leg imaginal disc in response to Dpp signaling. Here, we analyze the expression regulation and function of these genes during leg development. We have generated specific mutant alleles for each gene and a double fd4/fd5 mutant chromosome to study their function during development. We highlight the redundant role of the fd4/fd5 genes during the formation of the sex comb, a male specific structure that appears in the ventro-lateral domain of the prothoracic leg.

BAP1/ASXL complex modulation regulates Epithelial-Mesenchymal Transition during trophoblast differentiation and invasion

Normal function of the placenta depends on the earliest developmental stages when trophoblast cells differentiate and invade into the endometrium to establish the definitive maternal-fetal interface. Previously, we identified the ubiquitously expressed tumour suppressor BRCA1-associated protein 1 (BAP1) as a central factor of a novel molecular node controlling early mouse placentation. However, functional insights into how BAP1 regulates trophoblast biology are still missing. Using CRISPR/Cas9 knockout and overexpression technology, here we demonstrate that the downregulation of BAP1 protein is essential to trigger epithelial-mesenchymal transition (EMT) during trophoblast differentiation associated with a gain of invasiveness. This function, which is conserved in mouse and humans, is dependent on the binding of BAP1 binding to Additional sex comb-like (ASXL1/2/3) proteins to form the Polycomb repressive deubiquitinase (PR-DUB) complex. Our results reveal that the physiological modulation of BAP1 determines the invasive properties of trophoblast, delineating a new role of the BAP1 PR-DUB complex in regulating early placentation.

Sexual Selection Does Not Increase the Rate of Compensatory Adaptation to a Mutation Influencing a Secondary Sexual Trait in Drosophila melanogaster

Theoretical work predicts that sexual selection can enhance natural selection, increasing the rate of adaptation to new environments and helping purge harmful mutations. While some experiments support these predictions, remarkably little work has addressed the role of sexual selection on compensatory adaptation—populations’ ability to compensate for the costs of deleterious alleles that are already present. We tested whether sexual selection, as well as the degree of standing genetic variation, affect the rate of compensatory evolution via phenotypic suppression in experimental populations of Drosophila melanogaster. These populations were fixed for a spontaneous mutation causing mild abnormalities in the male sex comb, a structure important for mating success. We fine-mapped this mutation to an ∼85 kb region on the X chromosome containing three candidate genes, showed that the mutation is deleterious, and that its phenotypic expression and penetrance vary by genetic background. We then performed experimental evolution, including a treatment where opportunity for mate choice was limited by experimentally enforced monogamy. Although evolved populations did show some phenotypic suppression of the morphological abnormalities in the sex comb, the amount of suppression did not depend on the opportunity for sexual selection. Sexual selection, therefore, may not always enhance natural selection; instead, the interaction between these two forces may depend on additional factors.

The yellow gene influences Drosophila male mating success through sex comb melanization

Drosophila melanogaster males perform a series of courtship behaviors that, when successful, result in copulation with a female. For over a century, mutations in the yellow gene, named for its effects on pigmentation, have been known to reduce male mating success. Prior work has suggested that yellow influences mating behavior through effects on wing extension, song, and/or courtship vigor. Here, we rule out these explanations, as well as effects on the nervous system more generally, and find instead that the effects of yellow on male mating success are mediated by its effects on pigmentation of male-specific leg structures called sex combs. Loss of yellow expression in these modified bristles reduces their melanization, which changes their structure and causes difficulty grasping females prior to copulation. These data illustrate why the mechanical properties of anatomy, not just neural circuitry, must be considered to fully understand the development and evolution of behavior.

Diversity in external morphology, sex comb and developmental stages of three Drosophila species of melanogaster group

Samples of Drosophila species were collected from some selected sites (viz., Dohar Upazila of Dhaka Division, Hironpoint of the Sundarbans, Satchori of Sylhet Division) of Bangladesh and these were cultured in the laboratory to study developmental stages, external morphological traits and sex comb. They were identified as D. melanogaster, D. ananassae and D. bipectinata. The sex comb teeth number and arrangement were distinct for all three species. D. melanogaster had one row of 10 - 11 teeth in the sex comb. D. ananassae had eight rows of teeth in the sex comb possessing 32 - 33 teeth in total. D. bipectinata had 2 - 3 rows of teeth in the sex comb and total teeth number varied from 11 to 15. Among three species, sex comb teeth number of D. bipectinata varied most. Eleven different patterns (n=20) in sex comb were observed in D. bipectinata indicating significant diversity within species. Variation in pupation sites among three species was also observed in the laboratory condition. D. bipectinata pupated on the food medium, whereas other two species pupated on the vial wall. Thus, diversity among these three species of Drosophila was documented which could be utilized as bioindicator in future. Dhaka Univ. J. Biol. Sci. 28(2): 167-176, 2019 (July)

Sexual selection does not increase the rate of compensatory adaptation to a mutation influencing a secondary sexual trait inDrosophila melanogaster

Theoretical work predicts that sexual selection can enhance natural selection, increasing the rate of adaptation to new environments and helping purge harmful mutations. While some experiments support these predictions, remarkably little work has addressed the role of sexual selection on compensatory adaptation—populations’ ability to compensate for the costs of deleterious alleles that are already present. We tested whether sexual selection, as well as the degree of standing genetic variation, affect the rate of compensatory evolution via phenotypic suppression in experimental populations ofDrosophila melanogaster. These populations were fixed for a spontaneous mutation causing mild abnormalities in the male sex comb, a structure important for mating success. We fine-mapped this mutation to an ∼85 kb region on the X chromosome containing three candidate genes, showed that the mutation is deleterious, and that its phenotypic expression and penetrance vary by genetic background. We then performed experimental evolution, including a treatment where opportunity for mate choice was limited by experimentally enforced monogamy. Although evolved populations did show some phenotypic suppression of the morphological abnormalities in the sex comb, the amount of suppression did not depend on the opportunity for sexual selection. Sexual selection, therefore, may not always enhance natural selection; instead, the interaction between these two forces may depend on additional factors.