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Here, we perform an amino acid drop\u2010out screen and apply pre\u2010clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient\u2010derived CML CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells, rendering them arginine auxotrophic. Thus, arginine deprivation completely blocks proliferation of CML CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells and induces significantly higher levels of apoptosis when compared to arginine\u2010deprived cell lines. Similarly, primary CML cells, but not normal CD34\n                    <jats:sup>+<\/jats:sup>\n                    samples, are particularly sensitive to treatment with the arginine\u2010depleting enzyme, BCT\u2010100, which induces apoptosis and reduces clonogenicity. Moreover, BCT\u2010100 is highly efficacious in a patient\u2010derived xenograft model, causing &gt;\u200990% reduction in the number of human leukaemic stem cells (LSCs). These findings indicate arginine depletion to be a promising and novel strategy to eradicate therapy resistant LSCs.\n                  <\/jats:p>","DOI":"10.15252\/embr.202256279","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T07:42:15Z","timestamp":1690270935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0212-0017","authenticated-orcid":false,"given":"Kevin M","family":"Rattigan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0152-1599","authenticated-orcid":false,"given":"Martha M","family":"Zarou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Brabcova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7383-2460","authenticated-orcid":false,"given":"Bodhayan","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9sir\u00e9e","family":"Zerbst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4193-2464","authenticated-orcid":false,"given":"Daniele","family":"Sarnello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1108-6589","authenticated-orcid":false,"given":"Eric R","family":"Kalkman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1886-6614","authenticated-orcid":false,"given":"Angela","family":"Ianniciello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary T","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engy","family":"Shokry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9004-4079","authenticated-orcid":false,"given":"David","family":"Sumpton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mhairi","family":"Copland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5294-8683","authenticated-orcid":false,"given":"Saverio","family":"Tardito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Vande Voorde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-0047","authenticated-orcid":false,"given":"Francis","family":"Mussai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1616-132X","authenticated-orcid":false,"given":"G Vignir","family":"Helgason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"BFEMBR202256279_CR1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nature18288","volume":"534","author":"SA Abraham","year":"2016","unstructured":"Abraham SA, Hopcroft LEM, Carrick E, Drotar ME, Dunn K, Williamson AJK, Korfi K, Baquero P, Park LE, Scott MT et\u00a0al (2016) Dual targeting of p53 and c\u2010MYC selectively eliminates leukaemic stem cells. 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