{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:59:49Z","timestamp":1791500389800,"version":"4.3.4"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,11,7]]},"abstract":"<jats:p>\n                    It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph\n                    <jats:sup>+<\/jats:sup>\n                    ) chronic myeloid leukemia (CML) in chronic phase but not Ph\n                    <jats:sup>+<\/jats:sup>\n                    B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CML mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph\n                    <jats:sup>+<\/jats:sup>\n                    leukemia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0606509103","type":"journal-article","created":{"date-parts":[[2006,11,2]],"date-time":"2006-11-02T08:25:30Z","timestamp":1162455930000},"page":"16870-16875","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":226,"title":["Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph\n                    <sup>+<\/sup>\n                    leukemia in mice"],"prefix":"10.1073","volume":"103","author":[{"given":"Yiguo","family":"Hu","sequence":"first","affiliation":[{"name":"*The Jackson Laboratory, Bar Harbor, ME 04609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Swerdlow","sequence":"additional","affiliation":[{"name":"*The Jackson Laboratory, Bar Harbor, ME 04609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore M.","family":"Duffy","sequence":"additional","affiliation":[{"name":"*The Jackson Laboratory, Bar Harbor, ME 04609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Weinmann","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Oncology, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Oncology, Princeton, NJ 08543"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoguang","family":"Li","sequence":"additional","affiliation":[{"name":"*The Jackson Laboratory, Bar Harbor, ME 04609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,11,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104053441401"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.1.319"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-472X(00)00142-9"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062538"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1343"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.9.2808"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099480"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-05-1851"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.01.007"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104053441402"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V101.2.690"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.162140299"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-01-0288"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.9.1399"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206008"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.10.3780"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.8.2013.bloodjournal8582013"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V78.9.2178.2178"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.14.6293"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602030103"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.10.3792"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.4.1797"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.20.6.1692"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa055229"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-08-3373"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040258"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.23.6793"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.1.4"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(87)90745-8"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0606509103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T15:50:00Z","timestamp":1649778600000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0606509103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,11,7]]},"references-count":29,"journal-issue":{"issue":"45","published-print":{"date-parts":[[2006,11,7]]}},"alternative-id":["10.1073\/pnas.0606509103"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0606509103","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,11,7]]},"assertion":[{"value":"2006-08-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-11-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}