{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:10:40Z","timestamp":1778501440718,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,6]]},"group-title":"Cancer Biology","reference-count":78,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NCI Cancer Center","award":["P30 CA021765"],"award-info":[{"award-number":["P30 CA021765"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Aberrant activation of\n                  <jats:italic>TAL1<\/jats:italic>\n                  , a key oncogenic driver, defines a major subgroup comprising \u223c30% of childhood T-lineage acute lymphoblastic leukemias (T-ALLs). We and others have shown that somatic non-coding mutations within upstream and intronic\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory regions of\n                  <jats:italic>TAL1<\/jats:italic>\n                  contribute to transformation by creating binding sites for MYB and other transcription factors. Here we investigated\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory mechanisms mediated by somatic mutations occurring in an intergenic region located 29 kilobase pairs downstream of the canonical\n                  <jats:italic>TAL1<\/jats:italic>\n                  transcription initiation site, implicated in 6% of\n                  <jats:italic>TAL1<\/jats:italic>\n                  -expressing T-ALLs. These somatic variants include i) complex indels resulting in\n                  <jats:italic>de novo<\/jats:italic>\n                  MYB transcription factor binding sites (TFBSs) and ii) internal tandem duplications (ITDs) encompassing canonical MYB TFBSs. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed binding of the TAL1 core regulatory circuit (CRC) transcription factors MYB, GATA3, and RUNX1, resulting in enhancer activity mediated by sequences with the mutant allele. Strikingly, ChIP-seq peaks for the repressive H3K27me3 mark and the active H3K27ac mark co-existed across\n                  <jats:italic>TAL1<\/jats:italic>\n                  regulatory sequences but enriched for different haplotypes.\n                  <jats:italic>TAL1<\/jats:italic>\n                  transcription from the mutant haplotype initiated from a promoter located within exon 4 of the canonical\n                  <jats:italic>TAL1<\/jats:italic>\n                  transcript, resulting in a short isoform normally expressed by hematopoietic stem cells (HSC). Interestingly, neither the isoform expression nor the enhancer activity could be predicted by the sequence-to-function deep learning artificial intelligence (AI) model AlphaGenome, emphasizing the importance of experimental validation. Our findings indicate that selection for\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory, non-coding variants leads to reactivation of enhancers normally active in HSC but silenced in differentiated lineages during normal hematopoietic cell development.\n                <\/jats:p>","DOI":"10.64898\/2026.05.03.722504","type":"posted-content","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T04:00:23Z","timestamp":1778212823000},"source":"Crossref","is-referenced-by-count":0,"title":["Reactivation of a TAL1 progenitor cell enhancer region by non-coding somatic variants in T-lineage acute lymphoblastic leukemia"],"prefix":"10.64898","author":[{"given":"Nadezhda V.","family":"Terekhanova","sequence":"first","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"},{"name":"Pediatric Translational Medicine Institute, Shanghai Children\u2019s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kin-Hoe","family":"Chow","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bensheng","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinesh","family":"Vinayachandran","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haseeb","family":"Zubair","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wentao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sivaraman","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Easton","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, 38105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David T.","family":"Teachey","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Division of Oncology and Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"},{"name":"Department of Pediatrics and the Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. 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