{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T16:49:57Z","timestamp":1778086197565,"version":"3.51.4"},"reference-count":26,"publisher":"Proceedings of the National Academy of Sciences","issue":"16","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,8,6]]},"abstract":"<jats:p>\n            The Abl tyrosine kinase inhibitor STI-571 is effective therapy for stable phase chronic myeloid leukemia (CML) patients, but the majority of CML blast-crisis patients that respond to STI-571 relapse because of reactivation of Bcr-Abl signaling. Mutations of Thr-315 in the Abl kinase domain to Ile (T315I) were previously described in STI-571-resistant patients and likely cause resistance from steric interference with drug binding. Here we identify mutations of Tyr-253 in the nucleotide-binding (P) loop of the Abl kinase domain to Phe or His in patients with advanced CML and acquired STI-571 resistance. Bcr-Abl Y253F demonstrated intermediate resistance to STI-571\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            when compared with Bcr-Abl T315I. The response of Abl proteins to STI-571 was influenced by the regulatory state of the kinase and by tyrosine phosphorylation. The sensitivity of purified c-Abl to STI-571 was increased by a dysregulating mutation (P112L) in the Src homology 3 domain of Abl but decreased by phosphorylation at the regulatory Tyr-393. In contrast, the Y253F mutation dysregulated c-Abl and conferred intrinsic but not absolute resistance to STI-571 that was independent of Tyr-393 phosphorylation. The Abl P-loop is a second target for mutations that confer resistance to STI-571 in advanced CML, and the Y253F mutation may impair the induced-fit interaction of STI-571 with the Abl catalytic domain rather than sterically blocking binding of the drug. Because clinical resistance induced by the Y253F mutation might be overcome by dose escalation of STI-571, molecular genotyping of STI-571-resistant patients may provide information useful for rational therapeutic management.\n          <\/jats:p>","DOI":"10.1073\/pnas.162140299","type":"journal-article","created":{"date-parts":[[2002,9,30]],"date-time":"2002-09-30T16:42:53Z","timestamp":1033404173000},"page":"10700-10705","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":207,"title":["Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop"],"prefix":"10.1073","volume":"99","author":[{"given":"Sergei","family":"Roumiantsev","sequence":"first","affiliation":[{"name":"Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717; and Department of Medicine and Molecular Biology Institute, University of California, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678"}]},{"given":"Neil P.","family":"Shah","sequence":"additional","affiliation":[{"name":"Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717; and Department of Medicine and Molecular Biology Institute, University of California, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678"}]},{"given":"Mercedes E.","family":"Gorre","sequence":"additional","affiliation":[{"name":"Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717; and Department of Medicine and Molecular Biology Institute, University of California, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678"}]},{"given":"John","family":"Nicoll","sequence":"additional","affiliation":[{"name":"Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717; and Department of Medicine and Molecular Biology Institute, University of California, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678"}]},{"given":"Bradley B.","family":"Brasher","sequence":"additional","affiliation":[{"name":"Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717; and Department of Medicine and Molecular Biology Institute, University of California, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678"}]},{"given":"Charles L.","family":"Sawyers","sequence":"additional","affiliation":[{"name":"Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717; and Department of Medicine and Molecular Biology Institute, University of California, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678"}]},{"given":"Richard A.","family":"Van Etten","sequence":"additional","affiliation":[{"name":"Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717; and Department of Medicine and Molecular Biology Institute, University of California, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90024-1678"}]}],"member":"341","published-online":{"date-parts":[[2002,7,29]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"100","volume":"56","author":"Buchdunger E.","year":"1996","unstructured":"Buchdunger E., Zimmermann, J., Mett, H., Meyer, T., M\u00fcller, M., Druker, B. 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