Project description:Human tumors show aberrant RNA profiles that can originate from multiple pathways and mechanisms. One underexplored area is that alterations in RNA decapping, the addition of a 5´-end N7-methyl guanosine (m7G)-cap that is essential for stabilization of the RNA molecule, could also be involved in the distorted transcript landscape of cancer cells. Herein we show that the RNA editing enzyme NUDT16 undergoes promoter CpG island methylation-associated silencing in T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples. The restoration of in vitro and in vivo NUDT16 activity highlights the growth inhibitory features of the gene. Most importantly, we identify that the epigenetic loss of NUDT16 in leukemia cells prevents the RNA decay of growth-promoting genes, among them the C-MYC stabilizers FBXO28 and USP37, leading to higher levels of the oncogenic protein.
Project description:Proteogenomic analysis and genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of High hyperdiploid childhood acute lymphoblastic leukemia.
Project description:We quantitatively evaluated H2Bub and H3K79me2 epigenetic marks genome wide in a KMT2A rearranged B lineage acute lymphoblastic leukemia cell line after treatment with bortezomib over a 6 hour time course by ChIP-Rx. We identified rapid and concordant depletion of these epigenetic marks within two hours. To look at gene expression changes, RNA sequencing was performed on KMT2A rearranged B lineage acute lymphoblastic leukemia patient samples in the presence and absence of bortezomib exposure.
Project description:Proteogenomic analysis and genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of High hyperdiploid childhood acute lymphoblastic leukemia.
Project description:Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells and human JAK3 mutated T-ALL samples. Novel peptides shown to be downstream of mutant JAK3 regulating RNA metabolism as well as epigenetic and apoptotic processes were validated using targeted PRM proteomics.
