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Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation

Abstract

Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a(-/-) Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.

Type Journal
ISBN 1528-0020 (Electronic) 0006-4971 (Linking)
Authors Jacquelin, S.; Straube, J.; Cooper, L.; Vu, T.; Song, A.; Bywater, M.; Baxter, E.; Heidecker, M.; Wackrow, B.; Porter, A.; Ling, V.; Green, J.; Austin, R.; Kazakoff, S.; Waddell, N.; Hesson, L. B.; Pimanda, J. E.; Stegelmann, F.; Bullinger, L.; Dohner, K.; Rampal, R. K.; Heckl, D.; Hill, G. R.; Lane, S. W.
Publisher Name Blood
Published Date 2018-12-27
Published Volume 132
Published Issue 26
Published Pages 2707-2721
Status Published in-print
DOI 10.1182/blood-2018-04-846220
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/30366920