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dc.contributor.authorde Bock, Charles E
dc.contributor.authorDemeyer, Sofie
dc.contributor.authorDegryse, Sandrine
dc.contributor.authorVerbeke, Delphine
dc.contributor.authorSweron, Bram
dc.contributor.authorGielen, Olga
dc.contributor.authorVandepoel, Roel
dc.contributor.authorVicente, Carmen
dc.contributor.authorVanden Bempt, Marlies
dc.contributor.authorDagklis, Antonis
dc.contributor.authorGeerdens, Ellen
dc.contributor.authorBornschein, Simon
dc.contributor.authorGijsbers, Rik
dc.contributor.authorSoulier, Jean
dc.contributor.authorMeijerink, Jules P
dc.contributor.authorHeinäniemi, Merja
dc.contributor.authorTeppo, Susanna
dc.contributor.authorBouvy-Liivrand, Maria
dc.contributor.authorLohi, Olli
dc.contributor.authorRadaelli Enrico et al.
dc.date.accessioned2018-05-16T11:52:10Z
dc.date.available2018-05-16T11:52:10Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6611
dc.description.abstractLeukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells. Significance: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases.
dc.language.isoenglanti
dc.publisherAmerican Association for Cancer Research (AACR)
dc.relation.ispartofseriesCancer Discovery
dc.relation.urihttp://dx.doi.org/10.1158/2159-8290.CD-17-0583
dc.rightsAll rights reserved
dc.titleHOXA9 cooperates with activated JAK/STAT signaling to drive leukemia development
dc.description.versionfinal draft
dc.contributor.departmentSchool of Medicine / Biomedicine
uef.solecris.id53010312en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© American Association for Cancer Research
dc.relation.doi10.1158/2159-8290.CD-17-0583
dc.description.reviewstatuspeerReviewed
dc.format.pagerange616-631
dc.relation.issn2159-8274
dc.relation.issue5
dc.relation.volume8
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessEi


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