{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:23:20Z","timestamp":1768523000972,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,11]]},"group-title":"Cancer Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,11]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Despite therapeutic advances, high-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) such as Philadelphia chromosome-like (Ph-like) and\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -rearranged (\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -R) remain a formidable clinical challenge. BRG1 (gene name\n                  <jats:italic>SMARCA4<\/jats:italic>\n                  ), the ATPase subunit of the SWI\/SNF chromatin-remodeling complex, has been extensively studied in solid tumors, where inactivating mutations are linked to aggressive disease and poor prognosis. Although BRG1 is known to be essential for early B cell development, its role in B-ALL remains poorly understood. Therefore, we investigated the therapeutic relevance of BRG1 in high-risk B-ALL. Meta-analysis of gene expression data revealed that BRG1-inactivating mutations are exceedingly rare (0.35%) in B-ALL, suggesting that intact BRG1 function may be critical for leukemogenesis. Subtype-specific analyses revealed that elevated BRG1 expression is associated with significantly shorter overall survival in children with Ph-like B-ALL, while the opposite trend was observed in\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -R B-ALL. We confirmed higher BRG1 expressions in Ph-like compared to\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -R B-ALL via gene expression analysis, RT-PCR, and Western blotting. The pharmacologic inhibition of BRG1 using two selective inhibitors, BRM014 and FHD-286, revealed marked sensitivity in Ph-like B-ALL cell lines, whereas\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -R B-ALL was resistant. Mechanistically, we found that BRG1 inhibition results in cell cycle arrest via downregulation of cell cycle regulators (\n                  <jats:italic>CCND3, CDK4, CDK6, E2F1<\/jats:italic>\n                  , and\n                  <jats:italic>MYC) and<\/jats:italic>\n                  upregulation of the cell cycle inhibitor\n                  <jats:italic>CDKN1B<\/jats:italic>\n                  (p27). Importantly, treatment with FHD-286 significantly prolonged the survival of\n                  <jats:italic>NSG<\/jats:italic>\n                  mice engrafted with Ph-like B-ALL cells. Taken together, these findings establish BRG1 as a critical, subtype-specific dependency in Ph-like B-ALL and demonstrate that its pharmacologic inhibition effectively suppresses leukemic cell proliferation through induction of cell cycle arrest. The pronounced\n                  <jats:italic>in vitro<\/jats:italic>\n                  sensitivity and improved\n                  <jats:italic>in vivo<\/jats:italic>\n                  survival upon BRG1 inhibition provide compelling preclinical evidence for its therapeutic targeting. These results support the advancement of BRG1-directed strategies as a viable treatment approach for patients with Ph-like B-ALL, with the potential to improve outcomes in this high-risk population.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>\n                        Higher levels of BRG1 correlate to poor clinical outcomes in Ph-like but\n                        <jats:italic>KMT2A<\/jats:italic>\n                        -R B-ALL\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Inhibition of BRG1 induces cell cycle arrest in Ph-like cells\n                        <jats:italic>in vitro<\/jats:italic>\n                        and extends the survival of mice in pre-clinical\n                        <jats:italic>in vivo<\/jats:italic>\n                        studies\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                    <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"661805v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                    <\/jats:fig>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.08.661805","type":"posted-content","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T02:55:17Z","timestamp":1752288917000},"source":"Crossref","is-referenced-by-count":0,"title":["Selective Sensitivity of Ph-like B-ALL to BRG1 Inhibition Reveals a Novel Targeted Therapy Strategy"],"prefix":"10.64898","author":[{"given":"V. S. S. Abhinav","family":"Ayyadevara","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shikha","family":"Gaur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Paik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ria","family":"Perencsik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Toma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerald","family":"Wertheim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Geng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomasz","family":"Skorski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srividya","family":"Swaminathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8346-190X","authenticated-orcid":false,"given":"Christian","family":"Hurtz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025071408251615000_2025.07.08.661805v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.06.005"},{"key":"2025071408251615000_2025.07.08.661805v1.2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-422691"},{"key":"2025071408251615000_2025.07.08.661805v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1403088"},{"key":"2025071408251615000_2025.07.08.661805v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.375"},{"key":"2025071408251615000_2025.07.08.661805v1.5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.69.0073"},{"key":"2025071408251615000_2025.07.08.661805v1.6","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.136366"},{"key":"2025071408251615000_2025.07.08.661805v1.7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-07-726588"},{"key":"2025071408251615000_2025.07.08.661805v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(08)70339-5"},{"key":"2025071408251615000_2025.07.08.661805v1.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808253"},{"key":"2025071408251615000_2025.07.08.661805v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2015.38"},{"key":"2025071408251615000_2025.07.08.661805v1.11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-245944"},{"key":"2025071408251615000_2025.07.08.661805v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3068"},{"key":"2025071408251615000_2025.07.08.661805v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0357-3"},{"key":"2025071408251615000_2025.07.08.661805v1.14","doi-asserted-by":"publisher","DOI":"10.1101\/gad.232710.113"},{"key":"2025071408251615000_2025.07.08.661805v1.15","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01318"},{"key":"2025071408251615000_2025.07.08.661805v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0294-6"},{"key":"2025071408251615000_2025.07.08.661805v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3170"},{"key":"2025071408251615000_2025.07.08.661805v1.18","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-20-0011"},{"key":"2025071408251615000_2025.07.08.661805v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2532"},{"key":"2025071408251615000_2025.07.08.661805v1.20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103390"},{"key":"2025071408251615000_2025.07.08.661805v1.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019537108"},{"key":"2025071408251615000_2025.07.08.661805v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/nature10725"},{"key":"2025071408251615000_2025.07.08.661805v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.22944"},{"key":"2025071408251615000_2025.07.08.661805v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.216022"},{"key":"2025071408251615000_2025.07.08.661805v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2024.103472"},{"key":"2025071408251615000_2025.07.08.661805v1.26","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0061"},{"key":"2025071408251615000_2025.07.08.661805v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01159-z"},{"key":"2025071408251615000_2025.07.08.661805v1.28","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022832"},{"key":"2025071408251615000_2025.07.08.661805v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.02.011"},{"key":"2025071408251615000_2025.07.08.661805v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2513-4"},{"key":"2025071408251615000_2025.07.08.661805v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41375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