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Genetic dynamics in untreated chronic lymphocytic leukemia patients with either stable or progressive disease: a longitudinal study.

ABSTRACT: We investigated at two time points a longitudinal cohort of 27 untreated Chronic Lymphocytic Leukemia (CLL) patients with either stable or progressive disease. The sequenced genes included BCOR, EGR2, HIST1H1E, ITPKB, KRAS, MED12, NRAS, RIPK1, SAMHD1, ATM, BIRC3, BRAF, CHD2, DDX3X, DDX3Y, FBXW7, KIT, KLHL6, MAPK1, MYD88, NOTCH1, PIK3CA, POT1, SF3B1, TP53, XPO1 and ZMYM3, which were previously identified as mutated in CLL studies.

PROVIDER: PRJEB32802 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3346160.fastq.gz	Fastqsanger.gz
	ERR3346170.fastq.gz	Fastqsanger.gz
	ERR3346180.fastq.gz	Fastqsanger.gz
	ERR3346190.fastq.gz	Fastqsanger.gz
	ERR3346200.fastq.gz	Fastqsanger.gz

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Genetic dynamics in untreated chronic lymphocytic leukemia patients with either stable or progressive disease: a longitudinal study.

Project description:We investigated at two time points a longitudinal cohort of 27 untreated Chronic Lymphocytic Leukemia (CLL) patients with either stable or progressive disease. The sequenced genes included BCOR, EGR2, HIST1H1E, ITPKB, KRAS, MED12, NRAS, RIPK1, SAMHD1, ATM, BIRC3, BRAF, CHD2, DDX3X, DDX3Y, FBXW7, KIT, KLHL6, MAPK1, MYD88, NOTCH1, PIK3CA, POT1, SF3B1, TP53, XPO1 and ZMYM3, which were previously identified as mutated in CLL studies.

2019-11-05 | E-MTAB-8020 | biostudies-arrayexpress

APEX-seq performed for DDX3X and DDX3Y without arsenite treatment

Project description:Sex differences are pervasive in human health and disease. One of the major keys to sex-biased differences lies in the sex chromosomes, which encode a group of sex-specific protein homologs. Although the functions of the X chromosome proteins are well appreciated, how they compare with their Y chromosome homologs remains elusive. One pair of sex chromosome-encoded proteins are the RNA helicases DDX3X and DDX3Y. DDX3X and DDX3Y can both form stress granules (SGs) under different types of stress. SGs are composed of a stable core structure, they are surrounded by a dynamic shell with assembly, disassembly, and transitions of proteins and RNA between the core and shell. Different SGs have distinct proteins and RNA constituents, which raises the possibility that different SGs might perform different biological functions. Previously, we performed APEX-seq to explore the RNA compositions in DDX3X and DDX3Y SGs, however, the difference between the mRNA partner of DDX3X and DDX3Y without stress treatment is still uncharted. Therefore, we applied the APEX-seq to cytosome diffused DDX3X and DDX3Y.

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Transcriptome profiling of DDX3X/DDX3Y dependency after DDX3X gRNA targeting in KNS-42 parental cell lines, and rescue experiments with DDX3X or DDX3Y overexpressing cells (PACT).

Project description:Paralog dependency analysis of the DDX3X/DDX3Y genes through RNA-seq. Three types of KNS-42 cell lines are used in this experiment: one parental, one with a DDX3X over-expression (codon optimized) and one with DDX3Y over-expression (codon optimized). Targeting of the DDX3X gene is performed with guide RNAs 395 (TGGTACATGCGTATCCTTCA). The negative control is targeting AAVS1/PPP1R12C (AAVS1, GGGGCCACTAGGGACAGGAT). Samples were processed at 7 days after transduction. 3 independent repeats of the experiment were performed.

2022-04-06 | GSE190507 | GEO

Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate hollow condensates of DDX3X disease variants

Project description:The sex chromosome-encoded RNA helicases DDX3X and DDX3Y play important roles in RNA metabolism. Heterozygous mutations of DDX3X frequently occur in cancers and neurodevelopmental disorders which have strong sex biases. However, how different DDX3X variants impair cellular function in sex specific genetic background is not understood. Herein, we found that DDX3X variants with significantly impaired ATPase activities demixed into the shells of unique hollow condensates, the dynamics of which were further differentiated by the RNA binding affinities of the different DDX3X variants. Proteomic and imaging studies revealed that DDX3X variant condensates sequestered wild-type DDX3X, DDX3Y, and other proteins important for various signaling pathways. Intriguingly, wild-type DDX3X improved the dynamics of heterogenous variant/wild-type hollow condensates more than DDX3Y. These results suggest that DDX3X variants with distinct enzymatic and condensation propensities may interact uniquely with wild-type DDX3X or DDX3Y to cause sex-specific cellular impacts.

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Dissection of Richter’s syndrome pathogenesis and treatment through multiplexed CRISPR-based mouse models

Project description:Richter’s syndrome (RS) is a major obstacle to the management of patients with chronic lymphocytic leukemia (CLL). Its pathogenesis remains largely unknown, and presently, faithful cellular and mouse models are lacking. We report a novel congenic mouse model of RS, based on CRISPR-mediated introduction of multiplexed CLL loss-of-function lesions (i.e. Atm, Trp53, Samhd1, Mga, Birc3, Chd2) into del(13q) B cells, leading to recapitulation of disease features from CLL to transformation to RS, and exhibiting remarkable molecular and phenotypic similarity to human disease. By integrative genomic and functional analyses, we determine that mutation in Trp53, combined with Mga and Chd2, are necessary for RS transformation and for the dysregulation of E2F/MYC and interferon signaling pathways. We demonstrate that RS requires tonic PI3K signaling for survival, and shows vulnerability to MYC, CDK, mTOR and PI3K inhibitors. This model system presents a unique tool for the study of RS biology and therapy.

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APEX-seq Captures the Protein-RNA Interaction Patterns of DDX3X and DDX3Y

Project description:Although stress granules (SGs) are composed of a stable core structure, they are surrounded by a dynamic shell with assembly, disassembly, and transitions of proteins and RNA between the core and shell. Different SGs have distinct proteins and RNA constituents, which raises the possibility that different SGs might perform different biological functions. The RNA compositions of DDX3X- or DDX3Y-positive SGs are not known, nor is it known what differential effects DDX3X or DDX3Y may exert on these RNA components. To understand the biological function and the compositional differences between DDX3X- or DDX3Y-positive SGs, we first determined the RNA constituents in these SGs using an adapted Ascorbate-peroxidase (APEX)-based proximity labeling method. APEX converts exogenously supplied biotin-phenol (BP) to biotin-phenoxyl radicals, which in turn covalently labels protein and RNA in nanometers. APEX-mediated biotinylation has been widely used in studies of protein-protein interactions and recently in studying protein-RNA interactions. Here, we applied the APEX-mediated biotinylation in DDX3X and DDX3Y SGs to dissect their different RNA composition.

2022-06-01 | GSE171792 | GEO

CLL loss-of-function lesions distinctly impact B cell developmental and survival trajectories in B-cell restricted mouse models

Project description:Mouse models represent invaluable tools for the systematic evaluation of cancer drivers, yet those that address the impact of putative genetic drivers of chronic lymphocytic leukemia (CLL) on B cell development and function are largely lacking. To study recurrent loss-of-function (LOF) mutations observed in human CLL, we established a robust transplant model that can rapidly evaluate genetic lesions, based on CRISPR-Cas9–mediated gene knockout restricted to B cells. Using this system, we successfully generated six LOF-expressing models with B cell-specific depletion of Atm, Birc3, Trp53, Chd2, Samhd1 or Mga genes. Transcriptomic analyses identified presence of shared transcriptional networks associated with presence of the 6 modeled LOF mutations, related to increased B cell fitness in vitro and in vivo. We further identified a unique role for Mga in modulating B cell development through dysregulation of MYC and NOTCH signaling targets. None of the individual lesions led to CLL development, after 24 months of observation, supporting the relevance of combinatorial mutations for CLL development in vivo.

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