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Down syndrome acute lymphoblastic leukemia (DS\u2010ALL) is characterized by high frequency of\n                    <jats:italic>CRLF2<\/jats:italic>\n                    \u2010rearrangements,\n                    <jats:italic>JAK2<\/jats:italic>\n                    \u2010mutations, or RAS\u2010pathway mutations. Intriguingly,\n                    <jats:italic>JAK2<\/jats:italic>\n                    and\n                    <jats:italic>RAS<\/jats:italic>\n                    -mutations are mutually exclusive in leukemic sub\u2010clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS\u2010ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated\/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre\u2010inhibition of RAS or PTPN11, but not of PI3K or JAK\u2010signaling, prevented TSLP\u2010induced RAS\u2010GTP boost. Cytotoxicity assays on primary clinical DS\u2010ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS\u2010inhibitor or PTPN11-inhibitor, but not PI3K\/JAK\u2010inhibitors, suggesting a unified treatment target for up to 80% of DS\u2010ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein\u2010activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient\u2010stratification strategy for precision therapy in high-risk ALL.\n                  <\/jats:p>","DOI":"10.1038\/s41388-020-01567-7","type":"journal-article","created":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T11:03:04Z","timestamp":1606474984000},"page":"746-762","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2204-5165","authenticated-orcid":false,"given":"David","family":"Koschut","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8232-4062","authenticated-orcid":false,"given":"Debleena","family":"Ray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Giarin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Groet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8125-8198","authenticated-orcid":false,"given":"Ivan","family":"Ali\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley Kow-Yin","family":"Kham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wee Joo","family":"Chng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4607-8837","authenticated-orcid":false,"given":"Hany","family":"Ariffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Weinstock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen Eng-Juh","family":"Yeoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Basso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5486-5761","authenticated-orcid":false,"given":"Dean","family":"Ni\u017eeti\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"1567_CR1","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1016\/S0140-6736(12)62187-4","volume":"381","author":"H Inaba","year":"2013","unstructured":"Inaba H, Greaves M, Mullighan CG. 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