{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:15:41Z","timestamp":1785406541644,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,29]]},"group-title":"Cancer Biology","reference-count":104,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R21CA209229"],"award-info":[{"award-number":["R21CA209229"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA230618"],"award-info":[{"award-number":["R01CA230618"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  B-cell acute lymphoblastic leukemia (B-ALL) is driven by transcriptional dysregulation that impairs B-cell differentiation and sustains leukemic growth. A defining feature of high-risk B-ALL is mutations in\n                  <jats:italic>IKZF1<\/jats:italic>\n                  , which encodes the tumor suppressor IKAROS. Here, we map IKAROS gene regulatory networks in\n                  <jats:italic>IKZF1<\/jats:italic>\n                  -mutated Ph B-ALL using an inducible IKAROS system and multi-omic profiling. IKAROS restoration reprograms chromatin accessibility and transcriptional control, shifting regulation from an ETS-dominated state to one enriched for B-cell lineage factors. Among repressed transcription factors, we identify ERG as a key regulatory node directly bound and antagonized by IKAROS. IKAROS binds regulatory elements near\n                  <jats:italic>ERG<\/jats:italic>\n                  and other progenitor-associated genes, coinciding with reduced\n                  <jats:italic>ERG<\/jats:italic>\n                  expression and repression of transcriptional programs linked to early B-cell developmental stages. Analysis of single-cell multiome data from human B-cell progenitors shows that ERG and IKAROS have opposing stage-specific activities and identifies a developmental stage-specific regulatory region in\n                  <jats:italic>ERG<\/jats:italic>\n                  intron 3 which is bound by IKAROS, and functionally important for\n                  <jats:italic>ERG<\/jats:italic>\n                  gene expression. Functional assays using CRISPRi and ETS inhibitors, along with gene dependency data from DepMap, confirm ERG dependency in\n                  <jats:italic>IKZF1<\/jats:italic>\n                  -deficient B-ALL. Our findings identify ERG as a context-specific dependency in\n                  <jats:italic>IKZF1<\/jats:italic>\n                  -deficient B-ALL, providing a mechanistic basis for the observed mitigation of poor prognosis for\n                  <jats:italic>IKZF1<\/jats:italic>\n                  -mutation in patients with co-occurring\n                  <jats:italic>ERG<\/jats:italic>\n                  deletions.\n                <\/jats:p>","DOI":"10.64898\/2025.12.29.696402","type":"posted-content","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T05:10:13Z","timestamp":1767071413000},"source":"Crossref","is-referenced-by-count":0,"title":["IKAROS Gene Regulatory Network Reveal ERG as a Vulnerability in B-cell Acute Lymphoblastic Leukemia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4719-723X","authenticated-orcid":false,"given":"Hana","family":"Paculova","sequence":"first","affiliation":[{"name":"University of Vermont, Department of Biomedical and Health Sciences, Burlington, VT,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2148-2892","authenticated-orcid":false,"given":"Alyssa","family":"Richman","sequence":"additional","affiliation":[{"name":"University of Vermont, Department of Biomedical and Health Sciences, Burlington, VT,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8969-9676","authenticated-orcid":false,"given":"Joseph","family":"Boyd","sequence":"additional","affiliation":[{"name":"University of Vermont, Department of Biomedical and Health Sciences, Burlington, VT,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9261-8911","authenticated-orcid":false,"given":"Joshua Carlos","family":"Bernil","sequence":"additional","affiliation":[{"name":"University of California San Francisco, Department of Laboratory Medicine, San Francisco, CA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0790-9890","authenticated-orcid":false,"given":"Princess","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"University Vermont, Department of Molecular Genetics and Microbiology, Burlington, VT,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etapong","family":"Ayongaba","sequence":"additional","affiliation":[{"name":"University of California San Francisco, Department of Laboratory Medicine, San Francisco, CA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8640-5070","authenticated-orcid":false,"given":"Prachi","family":"Ghule","sequence":"additional","affiliation":[{"name":"University Vermont, Department of Biochemistry, Burlington, VT,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3481-4071","authenticated-orcid":false,"given":"Elsa","family":"Drivet","sequence":"additional","affiliation":[{"name":"University of Oslo, Institute of Clinical Medicine, Department of Immunology and KG Jebsen Center for B-cell Malignancies, Oslo, Norway,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-401X","authenticated-orcid":false,"given":"Amrita","family":"Palaria","sequence":"additional","affiliation":[{"name":"University of California San Francisco, Department of Laboratory Medicine, San Francisco, CA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Dajani","sequence":"additional","affiliation":[{"name":"University of California San Francisco, Department of Laboratory Medicine, San Francisco, CA,"},{"name":"University of Oslo, Institute of Clinical Medicine, Department of Immunology and KG Jebsen Center for B-cell Malignancies, Oslo, Norway,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Els","family":"Verhoeyen","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur, INSERM, C3M, 06204 Nice, France"},{"name":"CIRI \u2013 International Center for Infectiology Research, Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Sup\u00e9rieure de Lyon, Universit\u00e9 Lyon, F-69007, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6890-512X","authenticated-orcid":false,"given":"Anthony","family":"Saviola","sequence":"additional","affiliation":[{"name":"University of Colorado Denver Anschutz Medical Campus, Aurora, CO,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary S.","family":"Stein","sequence":"additional","affiliation":[{"name":"University Vermont, Department of Biochemistry, Burlington, 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