Project description:Serial transplantations using WT, Puma-/- , G3 mTerc-/-Puma+/+ and G3 mTerc-/-Puma-/- donors were used to analyze the effects of PUMA deficiency on the hematological phenotype of telomerase-deficient mice. RNAseq was performed to assess how downstream signaling was affected.
Project description:Clonal hematopoiesis (CH) in inherited bone marrow failure (BMF) is disease-specific but has been poorly characterized in telomere biology disorders (TBD).We studied the architecture, trajectories, and impact of CH in a cohort of 207 TBD patients and assessed the clinical relevance of molecular signatures linked to telomere dysfunction. Most patients (92%) had known germline mutations in TBD genes. CH was rare in asymptomatic but present in 46% of symptomatic patients, recurrently in PPM1D, POT1, TERT promoter (TERTp), and U2AF1. CH frequency increased with age and was significantly higher than in age- matched controls. CH in PPM1D/TERTp was enriched in TERT patients while CH in POT1 was enriched in TINF2 patients. CH in myelodysplastic syndromes (MDS)-related genes, most commonly splicing factors, was enriched in TERT/TERC patients. CH in TERTp, TP53 ̧ and MDS- related genes associated with poorer survival. Chromosome 1q (Chr1q) gain, and splicing factor gene (dominated by U2AF1S34/Q157R) or TP53 mutations increased the risk of MDS/acute myeloid leukemia (AML) development, regardless of allele burden. Trajectories with successive acquisition of MDS-related CH driven by U2AF1S34/Q157R were maladaptive, while adaptive CH involved branched POT1/PPM1D/TERTp trajectories. U2AF1S34/Q157R compensated aberrant TP53 and interferon-γ pathway activation that contribute to hematopoietic stem cell exhaustion in TBD.
Project description:DNA methylation profiling of 35 Telomere Biology Disorder (TBD) cases and 20 age-matched controls using the Infinium MethylationEPIC BeadChip arrays (Illumina). The cutoff for methylation differences between the cases and controls was set to |Δβ≥|0.2.