biostudies-literatureGiricz OPershing Square Sohn Cancer Research Alliance and Department of DefenseNCINCI NIH HHSNIHNIH HHS120422https://www.ebi.ac.uk/biostudies/studies/S-EPMC6124424biostudies-literatureUnknown3(14)Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexpression of the CSF 1 receptor (CSF1R) was seen in a majority of tumors and was driven by an alternative, endogenous viral promoter in a subset of samples. CSF1R was particularly elevated in melanomas with BRAF and other MAPK activating mutations. Furthermore, rebound ERK activation after BRAF inhibition was associated with RUNX1-mediated further upregulation of CSF-1R and its ligand IL-34. Importantly, increased CSF-1R and IL-34 overexpression weJCI insightThe RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma.PMC6124424P30 CA013330S10 OD019961W81XWH-14-1-0230SIG 1S10OD019961-01K12 CA090625P30CA013330Matusow BVardabasso CHabets GShellooe RWest BLBhagat TDBurton EZhang CMo YYu YBernstein ECotto-Rios XMTsai JGavathiotis EDahlman KBFields GBPradhan KPolishchuk VJohnson DBGreally JMNguyen HBollag GStanley ERBartenstein MKenny PASosman JAVerma AKGiricz OfalseThe RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma.Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexpression of the CSF 1 receptor (CSF1R) was seen in a majority of tumors and was driven by an alternative, endogenous viral promoter in a subset of samples. CSF1R was particularly elevated in melanomas with BRAF and other MAPK activating mutations. Furthermore, rebound ERK activation after BRAF inhibition was associated with RUNX1-mediated further upregulation of CSF-1R and its ligand IL-34. Importantly, increased CSF-1R and IL-34 overexpression we2018-01-01T00:00:00Z2018 Jul2026-04-29T02:57:32.173Z2019-03-26T23:54:58ZS-EPMC61244243004600510.1172/jci.insight.120422