{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T09:23:57Z","timestamp":1768037037050,"version":"3.49.0"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T00:00:00Z","timestamp":1605484800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T00:00:00Z","timestamp":1605484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001009","name":"Bristol-Myers Squibb Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009030","name":"Strategic Promotion of Innovative R and D","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009030","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic myeloid leukemia is driven by the BCR\u2010ABL oncoprotein, a constitutively active protein tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of CML patients, the emergence of TKI resistance is an important clinical problem, which deserves additional treatment options based on unique biological properties to CML cells. In this study, we show that metabolic homeostasis is critical for survival of CML cells, especially when the disease is in advanced stages. The BCR\u2010ABL protein activates AMP\u2010activated protein kinase (AMPK) for ATP production and the mTOR pathway to suppress autophagy. BCR\u2010ABL is detected in the nuclei of advanced\u2010stage CML cells, in which ATP is sufficiently supplied by enhanced glucose metabolism. AMP\u2010activated protein kinase is further activated under energy\u2010deprived conditions and triggers autophagy through ULK1 phosphorylation and mTOR inhibition. In addition, AMPK phosphorylates 14\u20103\u20103 and Beclin 1 to facilitate cytoplasmic translocation of nuclear BCR\u2010ABL in a BCR\u2010ABL\/14\u20103\u20103\u03c4\/Beclin1\/XPO1 complex. Cytoplasmic BCR\u2010ABL protein undergoes autophagic degradation when intracellular ATP is exhausted by disruption of the energy balance or forced autophagy flux with AMP mimetics, mTOR inhibitors, or arsenic trioxide, leading to apoptotic cell death. This pathway represents a novel therapeutic vulnerability that could be useful for treating TKI\u2010resistant CML.<\/jats:p>","DOI":"10.1111\/cas.14698","type":"journal-article","created":{"date-parts":[[2020,10,18]],"date-time":"2020-10-18T19:51:46Z","timestamp":1603050706000},"page":"194-204","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["AMP\u2010activated protein kinase activation primes cytoplasmic translocation and autophagic degradation of the BCR\u2010ABL protein in CML cells"],"prefix":"10.1111","volume":"112","author":[{"given":"Daisuke","family":"Koyama","sequence":"first","affiliation":[{"name":"Division of Stem Cell Regulation Center for Molecular Medicine Jichi Medical University Shimotsuke Japan"},{"name":"Department of Internal Medicine Fukushima Prefectural Miyashita Hospital Mishima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiro","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Regulation Center for Molecular Medicine Jichi Medical University Shimotsuke Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiaki","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Regulation Center for Molecular Medicine Jichi Medical University Shimotsuke Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatsugu","family":"Ohta","sequence":"additional","affiliation":[{"name":"Department of Hematology Fukushima Medical University Aizu Medical Center Aizuwakamatsu Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7249-6418","authenticated-orcid":false,"given":"Yusuke","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Regulation Center for Molecular Medicine Jichi Medical University Shimotsuke Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,11,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0512-y"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0490-0"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609324"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.21037\/sci.2016.07.08"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(19)30235-2"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020004834"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1009-1158"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0345"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-1613"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI73939"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.95"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aav3249"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0201-5"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-322537"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.212027"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13442"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx236"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-332783"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.194431"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401247"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.7.1999"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.186"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-11-610907"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80325"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2015.03.005"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddiscovery.2017.66"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.04.024"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2405057"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2405064"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90102-5"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.13.7457"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1228"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-402578"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201507634"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-01-0062"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18030537"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-018-0049-2"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2005.04765.x"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010409"},{"key":"e_1_2_8_41_1","first-page":"3443","article-title":"Beclin 1 contains a leucine\u2010rich nuclear export signal that is required for its autophagy and tumor suppressor function","volume":"61","author":"Liang XH","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-0846"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2018.06.001"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21076"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2152"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/84683"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-05-2123"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0042-2"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.14698","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.14698","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.14698","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.14698","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T15:00:39Z","timestamp":1693753239000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.14698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,16]]},"references-count":47,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1111\/cas.14698"],"URL":"https:\/\/doi.org\/10.1111\/cas.14698","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,16]]},"assertion":[{"value":"2020-06-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}