{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T23:30:11Z","timestamp":1792884611856,"version":"4.5.0"},"reference-count":53,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,10,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>IKAROS family zinc finger 1 (IKZF1) alterations represent a diverse group of genetic lesions that are associated with an increased risk of relapse in B-cell acute lymphoblastic leukemia. Due to the heterogeneity of concomitant lesions, it remains unclear how IKZF1 abnormalities directly affect cell function and therapy resistance, and whether their consideration as a prognostic indicator is valuable in improving outcome. CRISPR\/Cas9 strategies were used to engineer multiple panels of isogeneic lymphoid leukemia cell lines with a spectrum of IKZF1 lesions to measure changes in chemosensitivity, gene expression, cell cycle, and in vivo engraftment that can be linked to loss of IKAROS protein. IKZF1 knockout and heterozygous null cells displayed relative resistance to a number of common therapies for B-cell acute lymphoblastic leukemia, including dexamethasone, asparaginase, and daunorubicin. Transcription profiling revealed a stem\/myeloid cell\u2013like phenotype and JAK\/STAT upregulation after IKAROS loss. A CRISPR homology-directed repair strategy was also used to knock-in the dominant-negative IK6 isoform into the endogenous locus, and a similar drug resistance profile, with the exception of retained dexamethasone sensitivity, was observed. Interestingly, IKZF1 knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, likely owing to marked downregulation of SAMHD1 after IKZF1 knockout. Both types of IKZF1 lesions decreased the survival time of xenograft mice, with higher numbers of circulating blasts and increased organ infiltration. Given these findings, exact specification of IKZF1 status in patients may be a beneficial addition to risk stratification and could inform therapy.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002408","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T17:57:54Z","timestamp":1631037474000},"page":"3876-3890","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":11,"title":["Modeling\n                    <i>IKZF1<\/i>\n                    lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities"],"prefix":"10.1182","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1777-8516","authenticated-orcid":false,"given":"Jason H.","family":"Rogers","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"},{"name":"Stem Cells and Regenerative Medicine 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Therapy;"},{"name":"Stem Cells and Regenerative Medicine Center;"},{"name":"Department of Molecular and Human Genetics;"},{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldo","family":"Medrano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"},{"name":"Stem Cells and Regenerative Medicine Center;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Guzman","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy;"},{"name":"Stem Cells and Regenerative Medicine Center;"},{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogelio","family":"Aguilar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"},{"name":"Center for Cell and Gene Therapy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9076-3973","authenticated-orcid":false,"given":"Shannon E.","family":"Conneely","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tidie","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cade","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Barnes","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9321-4232","authenticated-orcid":false,"given":"Carlo D.D.","family":"Cristobal","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy;"},{"name":"Department of Molecular and Human Genetics;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Kurtz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, 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Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4096-6603","authenticated-orcid":false,"given":"Rachel E.","family":"Rau","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, and Texas Children\u2019s Hospital, Houston, TX;"},{"name":"Center for Cell and Gene Therapy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"issue":"5","key":"2022042221421421800_B1","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1080\/10428194.2017.1354372","article-title":"Advances in adult acute lymphoblastic leukemia therapy","volume":"59","author":"Aldoss","year":"2018","journal-title":"Leuk 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