{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:10:25Z","timestamp":1771373425795,"version":"3.50.1"},"reference-count":158,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2014,3,5]],"date-time":"2014-03-05T00:00:00Z","timestamp":1393977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>Tyrosine kinase inhibitors such as imatinib mesylate have changed the clinical course of chronic myeloid leukemia; however, the observation that these inhibitors do not target the leukemia stem cell implies that patients need to maintain lifelong therapy. The mechanism of this phenomenon is unclear: the question of whether tyrosine kinase inhibitors are inactive inside leukemia stem cells or whether leukemia stem cells do not require breakpoint cluster region (Bcr)-Abl signaling is currently under debate. Herein, I propose an alternative model: perhaps the leukemia stem cell requires Bcr-Abl, but is dependent on its kinase-independent functions. Kinases such as epidermal growth factor receptor and Janus kinase 2 possess kinase-independent roles in regulation of gene expression; it is worth investigating whether Bcr-Abl has similar functions. Mechanistically, Bcr-Abl is able to activate the Ras, phosphatidylinositol 3-kinase\/Akt, and\/or the Src-kinase Hck\/Stat5 pathways in a scaffolding-dependent manner. Whereas the scaffolding activity of Bcr-Abl with Grb2 is dependent on autophosphorylation, kinases such as Hck can use Bcr-Abl as substrate, inducing phosphorylation of Y177 to enable scaffolding ability in the absence of Bcr-Abl catalytic activity. It is worth investigating whether leukemia stem cells exclusively express kinases that are able to use Bcr-Abl as substrate. A kinase-independent role for Bcr-Abl in leukemia stem cells would imply that drugs that target Bcr-Abl's scaffolding ability or its DNA-binding ability should be used in conjunction with current therapeutic regimens to increase their efficacy and eradicate the stem cells of chronic myeloid leukemia<\/jats:p>\n               <\/jats:sec>","DOI":"10.5966\/sctm.2012-0159","type":"journal-article","created":{"date-parts":[[2014,3,6]],"date-time":"2014-03-06T05:40:04Z","timestamp":1394084404000},"page":"405-415","source":"Crossref","is-referenced-by-count":32,"title":["Kinase-Independent Mechanisms of Resistance of Leukemia Stem Cells to Tyrosine Kinase Inhibitors"],"prefix":"10.1093","volume":"3","author":[{"given":"Christine Victoria","family":"Ichim","sequence":"first","affiliation":[{"name":"Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Discipline of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada;"},{"name":"Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,3,5]]},"reference":[{"key":"2021122710013358500_R1","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1056\/NEJMoa022457","article-title":"Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia","volume":"348","author":"O'Brien","year":"2003","journal-title":"N Engl J Med"},{"key":"2021122710013358500_R2","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1056\/NEJMoa030513","article-title":"Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia","volume":"349","author":"Hughes","year":"2003","journal-title":"N Engl J 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