{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T14:37:58Z","timestamp":1777905478730,"version":"3.51.4"},"reference-count":63,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["The CRISPR Journal"],"published-print":{"date-parts":[[2021,8,1]]},"abstract":"<jats:p>\n                    Chronic myeloid leukemia (CML) is a hematopoietic malignancy produced by a unique oncogenic event involving the constitutively active tyrosine-kinase (TK)\n                    <jats:italic toggle=\"yes\">BCR\/ABL1<\/jats:italic>\n                    . TK inhibitors (TKI) changed its prognosis and natural history. Unfortunately,\n                    <jats:italic toggle=\"yes\">ABL1<\/jats:italic>\n                    remains unaffected by TKIs. Leukemic stem cells (LSCs) remain, and resistant mutations arise during treatment. To address this problem, we have designed a therapeutic CRISPR-Cas9 deletion system targeting\n                    <jats:italic toggle=\"yes\">BCR\/ABL1<\/jats:italic>\n                    . The system was efficiently electroporated to cell lines, LSCs from a CML murine model, and LSCs from CML patients at diagnosis, generating a specific\n                    <jats:italic toggle=\"yes\">ABL1<\/jats:italic>\n                    null mutation at high efficiency and allowing the edited leukemic cells to be detected and tracked. The CRISPR-Cas9 deletion system triggered cell proliferation arrest and apoptosis in murine and human CML cell lines. Patient and murine-derived xenografts with CRISPR-edited LSCs in NOD SCID gamma niches revealed that normal multipotency and repopulation ability of CRISPR edited LSCs were fully restored. Normal hematopoiesis was restored, avoiding myeloid bias. To the best of our knowledge, we show for the first time how a CRISPR-Cas9 deletion system efficiently interrupts\n                    <jats:italic toggle=\"yes\">BCR\/ABL1<\/jats:italic>\n                    oncogene in primary LSCs to bestow a therapeutic benefit. This study is a proof of concept for genome editing in all those diseases, like CML, sustained by a single oncogenic event, opening up new therapeutic opportunities.\n                  <\/jats:p>","DOI":"10.1089\/crispr.2021.0009","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T10:00:55Z","timestamp":1629280855000},"page":"519-535","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":8,"title":["CRISPR-Cas9 Technology as a Tool to Target Gene Drivers in Cancer: Proof of Concept and New Opportunities to Treat Chronic Myeloid Leukemia"],"prefix":"10.1177","volume":"4","author":[{"given":"Elena","family":"Vuelta","sequence":"first","affiliation":[{"name":"Unidad de Diagn\u00f3stico Molecular y Celular del C\u00e1ncer, Instituto Biolog\u00eda Molecular y Celular del C\u00e1ncer (USAL\/CSIC), Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Servicio de Transg\u00e9nesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Luis","family":"Ordo\u00f1ez","sequence":"additional","affiliation":[{"name":"Unidad de Diagn\u00f3stico Molecular y Celular del C\u00e1ncer, Instituto Biolog\u00eda Molecular y Celular del C\u00e1ncer (USAL\/CSIC), Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"IBSAL, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f3nica","family":"Alonso-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Unidad de Diagn\u00f3stico Molecular y Celular del C\u00e1ncer, Instituto Biolog\u00eda Molecular y Celular del C\u00e1ncer (USAL\/CSIC), Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"IBSAL, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc\u00eda","family":"M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Servicio de Transg\u00e9nesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Hern\u00e1ndez-Carabias","sequence":"additional","affiliation":[{"name":"Servicio de Transg\u00e9nesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Salda\u00f1a","sequence":"additional","affiliation":[{"name":"Servicio de Hematolog\u00eda, Hospital de Jerez, C\u00e1diz, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juli\u00e1n","family":"Sevilla","sequence":"additional","affiliation":[{"name":"Hospital Infantil Universitario Ni\u00f1o Jes\u00fas, Madrid, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Sebasti\u00e1n","sequence":"additional","affiliation":[{"name":"Hospital Infantil Universitario Ni\u00f1o Jes\u00fas, Madrid, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Munti\u00f3n","sequence":"additional","affiliation":[{"name":"Unidad de Diagn\u00f3stico Molecular y Celular del C\u00e1ncer, Instituto Biolog\u00eda Molecular y Celular del C\u00e1ncer (USAL\/CSIC), Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Hospital Infantil Universitario Ni\u00f1o Jes\u00fas, Madrid, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"RETIC TerCel y CIBERONC, ISCIII, Madrid, Spain; and Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Servicio de Hematolog\u00eda, Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferm\u00edn","family":"S\u00e1nchez-Guijo","sequence":"additional","affiliation":[{"name":"Unidad de Diagn\u00f3stico Molecular y Celular del C\u00e1ncer, Instituto Biolog\u00eda Molecular y Celular del C\u00e1ncer (USAL\/CSIC), Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Hospital Infantil Universitario Ni\u00f1o Jes\u00fas, Madrid, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"RETIC TerCel y CIBERONC, ISCIII, Madrid, Spain; and Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Servicio de Hematolog\u00eda, Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas Mar\u00eda","family":"Hern\u00e1ndez-Rivas","sequence":"additional","affiliation":[{"name":"Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"IBSAL, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Servicio de Hematolog\u00eda, Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Garc\u00eda-Tu\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"Unidad de Diagn\u00f3stico Molecular y Celular del C\u00e1ncer, Instituto Biolog\u00eda Molecular y Celular del C\u00e1ncer (USAL\/CSIC), Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"IBSAL, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"S\u00e1nchez-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"Servicio de Transg\u00e9nesis, NUCLEUS, Universidad de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."},{"name":"IBSAL, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, Salamanca, Spain; Hospital Universitario de Salamanca, Salamanca, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3460176"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(76)90970-3"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-015-0143-7"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.179.1.167"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.180399"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(84)90438-0"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.6.1810"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.12.7587"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.11.4.1785"},{"key":"e_1_3_5_11_2","first-page":"1728","article-title":"SH1 domain autophosphorylation of P210 BCR\/ABL is required for transformation but not growth factor independence","volume":"13","author":"Pendergast AM","year":"1993","unstructured":"Pendergast AM, , Gishizky ML, , Havlik MH, et al. SH1 domain autophosphorylation of P210 BCR\/ABL is required for transformation but not growth factor independence. Mol Cell Biol, 1993; 13:1728\u20131736. DOI: 10.1128\/mcb.13.3.1728.","journal-title":"Mol Cell Biol"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201053"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7939633"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/363045a0"},{"key":"e_1_3_5_15_2","first-page":"247","article-title":"Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia","volume":"13","author":"Shuai K","year":"1996","unstructured":"Shuai K, , Halpern J, , ten Hoeve J, et al. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. 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