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Mutation in familial platelet disorder with predisposition to myeloid malignancies

ABSTRACT: Mutation in familial platelet disorder with predisposition to myeloid malignancies

PROVIDER: PRJEB27365 | ENA |

REPOSITORIES: ENA

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Transcription profiling of human CD34+ cells from familial platelet disorder

Project description:Characterize the genes deregulated in CD34 positive cells from peripheral blood of FPD/AML patients harbouring two different RUNX1 mutations. RUNX1 (also called AML1), a DNA-binding subunit of the CBF transcription factor family, is a master regulatory gene in hematopoiesis and acts as a tumour suppressor. Heterozygous germ line alterations in RUNX1 lead to a familial platelet disorder with a propensity to develop acute myeloid leukemia (FPD/AML). Although RUNX1 abnormalities per se are not sufficient to induce full-blown leukemia in FPD, this pathology represents a valuable model to understand how RUNX1 germ line mutations predispose to acquisition of additional genetic changes leading to leukemia transformation. To investigate how RUNX1 may predispose to leukemia, we performed a comparative study between two pedigrees harbouring different RUNX1 mutations, one associated with only thrombocytopenia (R139stop) and the other leading to thrombocytopenia and leukemic predisposition (R174Q).

2010-09-11 | E-TABM-792 | biostudies-arrayexpress

Mutation in familial platelet disorder with predisposition to myeloid malignancies

Project description:Detection of causal variant for thrombocytopenia and second hit causing malignant disease onset by next-generation sequencing. The sample was taken at MDS diagnosis, the illness later developed into AML.

2018-06-29 | E-MTAB-6899 | biostudies-arrayexpress

Kids First Pediatric Research Study in Familial Predisposition to Hematopoietic Malignancies (SJFAMILY-HM)

Project description:Kids First Pediatric Research Study in Familial Predisposition to Hematopoietic Malignancies (SJFAMILY-HM)

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Kids First Pediatric Research Study in Familial Predisposition to Hematopoietic Malignancies (SJFAMILY-HM)

Project description:Kids First Pediatric Research Study in Familial Predisposition to Hematopoietic Malignancies (SJFAMILY-HM)

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A familial disorder of altered DNA-methylation

2014-07-01 | GSE47879 | GEO

A familial disorder of altered DNA-methylation

Project description:In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. We have investigated the clinical and molecular features of a familial DNA methylation disorder. Bisulphite converted DNA from the 60 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip

2014-07-01 | E-GEOD-47879 | biostudies-arrayexpress

Defective RNA helicase genes underlie predisposition to colorectal and hematological malignancies

Project description:Background: Causative genes are mostly unknown for the mismatch repair-proficient category of familial colorectal cancers designated as FCCTX. Recent evidence suggests shared susceptibility factors between colorectal and hematological malignancies. Study design: We investigated 28 FCCTX families by exome sequencing, supplemented with whole genome sequencing, RNA-sequencing, and tumor studies to identify the predisposing genes. Guided by the findings, germline and somatic exomes of ~400 patients with acute leukemia, myelodysplastic syndrome, and myeloma were subsequently examined. Results: A family with hematological and solid malignancies revealed a truncating variant in the DEAH-box RNA helicase gene DHX40 co-segregating with disease in seven family members. Neoplastic tissues revealed no apparent “second hit”, implying a haploinsufficiency model of tumorigenesis. DHX40 siRNA-treated cell lines exhibited a 13% increase in aberrantly spliced transcripts vs. GAPDH-siRNA or non-target siRNA-treated cells. Two additional families showed truncating germline variants in the TDRD9 and TDRD5 genes encoding Tudor domain-containing RNA-binding proteins. In the hospital-based hematological series, 18% of germline and 28% of somatic exomes revealed possibly pathogenic DEAD/H box gene variants, including somatic variants of DHX40 in four. Conclusions: This study identifies DHX40, TDRD9, and TDRD5 as novel candidate genes for FCCTX predisposition. In the family segregating the truncating DHX40 variant, two carriers had hematological neoplasia, suggesting possible analogy to DDX41, a DEAD-box RNA helicase gene previously linked to myeloid malignancies. Our findings emphasize aberrant RNA metabolism behind FCCTX and hematological neoplasia.

2023-11-08 | GSE228991 | GEO

A Critical Role of RUNX1 in Governing Megakaryocyte-Primed Hematopoietic Stem Cell Differentiation [10x scRNAseq]

Project description:RUNX1 is crucial for multiple stages of hematopoiesis and its mutation can cause familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). We aim to study the role of RUNX1 in megakaryocyte-biased HSCs differentiation to megakaryocytes.

2023-01-20 | GSE211861 | GEO

A Critical Role of RUNX1 in Governing Megakaryocyte-Primed Hematopoietic Stem Cell Differentiation [Single MK RNAseq]

2023-01-20 | GSE211937 | GEO

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). [ChIP-Seq]

Project description:Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

2024-02-01 | GSE252739 | GEO

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