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

Item Type:	Article
Title:	Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation
Creators Name:	Jacquelin, S. and Straube, J. and Cooper, L. and Vu, T. and Song, A. and Bywater, M. and Baxter, E. and Heidecker, M. and Wackrow, B. and Porter, A. and Ling, V. and Green, J. and Austin, R. and Kazakoff, S. and Waddell, N. and Hesson, L.B. and Pimanda, J.E. and Stegelmann, F. and Bullinger, L. and Döhner, K. and Rampal, R.K. and Heckl, D. and Hill, G.R. and Lane, S.W.
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.
Keywords:	Amino Acid Substitution, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, Hematologic Neoplasms, Hematopoietic Stem Cells, Janus Kinase 2, Missense Mutation, Mutant Strains Mice, Primary Myelofibrosis, Signal Transduction, Animals, Mice
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	132
Number:	26
Page Range:	2707-2721
Date:	27 December 2018
Official Publication:	https://doi.org/10.1182/blood-2018-04-846220
PubMed:	View item in PubMed

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