Project description:Genome wide DNA methylation profiling of pediatric acute myeloid leukemia obtained from bone marrow. The Illumina EPIC methylation beadchip array was used to obtain DNA methylation profiles across approximately 850,000 CpG dinucleotide methylation loci in DNA isolated from leukemia. Samples include 64 patients.
Project description:Acute promyelocytic leukemia (APL) is categorized as the M3 subtype in the French-American-British classification system. It represents a unique subtype of acute myeloid leukemia (AML) characterized by the t(15;17)/PML::RARA fusion, with leukemic cells arrested at the promyelocytic stage of myelopoiesis. Pediatric APL accounts for approximately 5%-10% of all AML. While the prognosis of APL patients has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide, relapse patients still exist. To reveal the molecular biological basis of pediatric APL, we performed an integrative analysis of the trasncriptome and methylome.
Project description:Acute myeloid leukemia (AML) in children with cytogenetic aberrations like translocation t(7;12)(q36;p13) is associated with inferior outcome. The translocation can lead to a fusion transcript MNX1::ETV6 but also to activation of MNX1 transcription. We generated an AML mouse model by transplantation of fetal liver cells with ectopic expression of MNX1. AML was highly penetrant in immunocompromised and less penetrant in immunocompetent mice. Transforming capacity was restricted to fetal liver cells and could not achieved with adult bone marrow cells, in concordance with the clinical finding that t(7;12)(q36;p13) is mostly restricted to infants. Ectopic expression of MNX1 led to increased H3K4methylation and reduced H3K27me3, possibly through its interaction with methyl transferases. MNX1 expression was accompanied with changes in genome wide chromatin accessibility , increased DNA damage, depletion in the LSK population and skewing toward the myeloid lineage. These effects, together with leukemia development, could be prevented by the S-adenosylmethionine analogue Sinefungin that acts as a SAM competitor and a pan methyltranferases inhibitor. Expression profiles of a human iPSC AML model with t(7;12) and of TARGET pediatric AML and TCGA patients support the rationale for targeting MNX1 and downstream pathways.
Project description:Acute promyelocytic leukemia (APL) is categorized as the M3 subtype in the French-American-British classification system. It represents a unique subtype of acute myeloid leukemia (AML) characterized by the t(15;17)/PML::RARA fusion, with leukemic cells arrested at the promyelocytic stage of myelopoiesis. Pediatric APL accounts for approximately 5%-10% of all AML. While the prognosis of APL patients has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide, relapse patients still exist. To reveal the molecular biological basis of pediatric APL, we performed an integrative analysis of the trasncriptome and methylome.
Project description:Chemotherapy resistance and relapse remain major challenges in pediatric acute myeloid leukemia (pAML), particularly in acute megakaryoblastic leukemia (AMKL) driven by the CBFA2T3-GLIS2 (C/G) fusion. To investigate the epigenetic mechanisms contributing to these challenges, we employed multi-epigenomic approaches to identify oncogenic enhancers at cis-regulatory elements (CREs) that drive aberrant gene expression.
Project description:We established a transcriptome cohort of pediatric acute myeloid leukemia (n=553) with RNA sequencing. This dataset of cord blood CD34+ cells (n=5, indivisual lots) is normal controls to characterize leukemia-specific expression patterns.