Existing compendia of non-coding RNA (ncRNA) are incomplete, in part because they are derived almost exclusively from small and polyadenylated RNAs. Here we present a more comprehensive atlas of the human transcriptome, which includes small and polyA RNA as well as total RNA from 300 human tissues and cell lines. We report thousands of previously uncharacterized RNAs, increasing the number of documented ncRNAs by approximately 8%. To infer functional regulation by known and newly characterized ncRNAs, we exploited pre-mRNA abundance estimates from total RNA sequencing, revealing 316 microRNAs and 3,310 long non-coding RNAs with multiple lines of evidence for roles in regulating protein-coding genes and pathways. Our study both refines and expands the current catalog of human ncRNAs and their regulatory interactions. All data, analyses and results are available for download and interrogation in the R2 web portal, serving as a basis for future exploration of RNA biology and function.
Mutations in occur in myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). mutations cluster at proline 95, with the most frequent mutation being a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease, and have been identified in age-related clonal hemopoiesis. It is not clear how mutation of modifies hemopoiesis or contributes to the development of myeloid bias or MDS/MPN. Two prior mouse models of mutation have been reported; however, these models do not recapitulate many of the clinical features of -mutant disease and relied on bone marrow (BM) transplantation stress to elicit the reported phenotypes. We describe a new conditional murine mutation model, where the P95H mutation is expressed physiologically and heterozygously from its endogenous locus after Cre activation. Using multiple Cre lines, we demonstrate that during native hemopoiesis (ie, no BM transplantation), the mutation needs to occur within the hemopoietic stem-cell-containing populations to promote myelomonocytic bias and expansion with corresponding transcriptional and RNA splicing changes. With age, nontransplanted animals developed a progressive, transplantable disease characterized by myeloid bias, morphological dysplasia, and monocytosis, hallmarks of MDS/MPN in humans. Analysis of cooccurring mutations within the BM demonstrated the acquisition of additional mutations that are recurrent in humans with mutations. The tractable knock-in model we have generated is highly relevant to human disease and will serve to elucidate the effect of mutations on initiation and maintenance of MDS/MPN.
Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies by mapping transcribed HERV genes and generating a library of 1169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Using DNA barcode-labeled MHC-I multimers, we find CD8+ T cell populations recognizing 29 HERV-derived peptides representing 18 different HERV loci, of which HERVH-5, HERVW-1, and HERVE-3 have more profound responses; such HERV-specific T cells are present in 17 of the 34 patients, but less frequently in healthy donors. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients; meanwhile DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study thus uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies.
Widespread and recurrent alternative splicing differences exist between AML patients with good or poor prognosis Missplicing of RNA splicing factors leads to altered splicing of their target transcripts Aberrant splicing of protein translation genes triggers the induction of an integrated stress response and concomitant inflammatory response Alternative RNA splicing information can be used to improve the accuracy of existing prognostic algorithms in AML The addition of the splicing signature accurately classifies ELN Int AML patients, effectively converting a three-group classification system into a twogroup one, facilitating better treatment decisions to be made. Translational RelevanceUtilising cytogenetic and mutational information, the European LeukemiaNet (ELN) algorithm is the clinical standard for prognosis in AML. However, there is considerable room for improvement, especially in patients classified as intermediaterisk for whom treatment is challenging. The 4-gene splicing signature that we have discovered improves the accuracy of classification, converting the existing threegroup risk classification (favorable, intermediate and adverse-risk) into essentially two groups with significantly different overall survival. This will facilitate improved treatment decisions to be made for patients.Our findings also reveal new molecular vulnerabilities that can be potential drug targets for the treatment of AML, a disease that currently has poor overall outcomes (<30% five-year survival rate). Direct pharmacological inhibition of splicing factors is potentially challenging clinically due to the toxicity of the drugs. Our data suggests that targeting integrated stress response or pathways stimulated as a consequence of missplicing in leukemic cells could be an alternative approach.Research.
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