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


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.; Döhner, K.; Rampal, R. K.; Heckl, D.; Hill, G. R.; Lane, S. W.
Article Title: 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 Dnmt3a2/2 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. © 2018 by The American Society of Hematology; all rights reserved.
Journal Title: Blood
Volume: 132
Issue: 26
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-12-27
Start Page: 2707
End Page: 2721
Language: English
DOI: 10.1182/blood-2018-04-846220
PUBMED: 30366920
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 1 February 2019 -- Source: Scopus
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  1. Raajit Kumar Rampal
    125 Rampal