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MYD88/TLR mutations in CLL

ABSTRACT: The Chronic Lymphocytic Leukemia (CLL) Genome Project aims to identify genetic alterations involved in the development and progression of the CLL, which are still unknown, with the objective of generating a comprehensive catalogue of genetic alterations in 500 independent tumours. The CLL Genome Project, as a contributing member of the International Cancer Genome Consortium (ICGC), has the purposes of creating diagnostic tools, discovering therapeutic targets and developing new strategies that will allow a customized therapy for CLL in order to make it more precise and effective.

PROVIDER: EGAS00001000772 | EGA |

REPOSITORIES: EGA

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Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome.

Martínez-Trillos Alejandra A Pinyol Magda M Navarro Alba A Aymerich Marta M Jares Pedro P Juan Manel M Rozman María M Colomer Dolors D Delgado Julio J Giné Eva E González-Díaz Marcos M Hernández-Rivas Jesús M JM Colado Enrique E Rayón Consolación C Payer Angel R AR Terol Maria José MJ Navarro Blanca B Quesada Victor V Puente Xosé S XS Rozman Ciril C López-Otín Carlos C Campo Elías E López-Guillermo Armando A Villamor Neus N

Blood 20140429 24

Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and ...[more]

PMID: 24782504

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CLL Genome

Project description:The Chronic Lymphocytic Leukemia (CLL) Genome Project aims to identify genetic alterations involved in the development and progression of the CLL, which are still unknown, with the objective of generating a comprehensive catalogue of genetic alterations in 500 independent tumours. The CLL Genome Project, as a contributing member of the International Cancer Genome Consortium (ICGC), has the purposes of creating diagnostic tools, discovering therapeutic targets and developing new strategies that will allow a customized therapy for CLL in order to make it more precise and effective. This study consists of two datasets. EGAD00001000023 described in the Nature paper (2011), Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia, and the dataset EGA00001000044 & & EGAD00001000083 described in the Nature (2011) paper, Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.Additional data generated within the ICGC-CLL genome project can be found in studies EGAS00001000374 and EGAS00001001306

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Active AKT Signaling triggers CLL towards Richter's transformation via over-activation of Notch1

Project description:Richter's syndrome (RS) is an aggressive transformation of Chronic Lymphocytic Leukaemia (CLL) frequently due to TP53, CDKN2, MYC or NOTCH1 mutations. whereas a significant proportion displays no specifically acquired driver mutation. We observe constitutive AKT phosphorylation not only in high-risk CLL patients harbouring p53 and NOTCH mutations but also in numerous RS patients. Consistently, genetic over-activation of AKT within the Eµ-TCL1 CLL mouse model results in a high-grade lymphoma phenotype of Richters syndrome. Multiomics assessment of our novel mouse model revealed a S100 defined subcluster of highly proliferative lymphoma cells developing from indolent CLL-like B-cells as a consequence of sudden NOTCH activation being fueled by enhanced NOTCH ligand exposure from T-cells in the microenvironment. Our data link AKT and NOTCH signaling in patient samples, genomic alterations, phosphoproteome and single-cell transcriptome profiles. Collectively, we have identified active AKT as a causative transforming pathway of indolent CLL towards aggressive RS thus providing novel mechanistic insights into the molecular understanding of RS.

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Project description:We examined copy number changes in the genomes of B cells from 58 patients with chronic lymphocytic leukemia (CLL) using representational oligonucleotide microarray analysis (ROMA), a form of comparative genomic hybridization (CGH), at a resolution exceeding previously published studies. We observed at least one genomic lesion in each CLL sample and considerable variation in the number of abnormalities from case to case. Virtually all abnormalities previously reported were also observed here, most of whichwere indeed highly recurrent. We observed the boundaries of known events with greaterclarity and identified previously undescribed lesions, some of which were recurrent. Weprofiled the genomes of CLL cells separated by the surface marker CD38, and foundevidence of distinct subclones of CLL within the same patient. We discuss the potential applications of high resolution CGH analysis in a clinical setting. Keywords: Genetic modification, polymorphonuclear cell (PMN)

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Genomic Alterations in High-risk CLL Frequently Affect Cell Cycle Key Regulators and NOTCH1‑regulated Transcription.

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