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Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor \u03b1 chain (IL-7R\u03b1, encoded by <jats:italic>IL7R<\/jats:italic>), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, which genes cooperate with <jats:italic>IL7R<\/jats:italic> to drive leukemogenesis remain poorly defined. Here, we demonstrate that mutant <jats:italic>IL7R<\/jats:italic> alone is capable of inducing T-ALL with long-latency in stable transgenic zebrafish and transformation is associated with <jats:italic>MYC<\/jats:italic> transcriptional activation. Additionally, we find that mutant <jats:italic>IL7R<\/jats:italic> collaborates with Myc to induce early onset T-ALL in transgenic zebrafish, supporting a model where these pathways collaborate to drive leukemogenesis. T-ALLs co-expressing mutant <jats:italic>IL7R<\/jats:italic> and <jats:italic>Myc<\/jats:italic> activate STAT5 and AKT pathways, harbor reduced numbers of apoptotic cells and remake tumors in transplanted zebrafish faster than T-ALLs expressing Myc alone. Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant <jats:italic>IL7R<\/jats:italic> and Myc in inducing T-ALL and demonstrates that mutant <jats:italic>IL7R<\/jats:italic> enriches for leukemia propagating potential.<\/jats:p>","DOI":"10.1038\/s41375-022-01590-5","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T12:15:47Z","timestamp":1652789747000},"page":"1533-1540","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"36","author":[{"given":"Mariana L.","family":"Oliveira","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-7578","authenticated-orcid":false,"given":"Alexandra","family":"Veloso","sequence":"additional","affiliation":[]},{"given":"Elaine G.","family":"Garcia","sequence":"additional","affiliation":[]},{"given":"Sowmya","family":"Iyer","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9519-2310","authenticated-orcid":false,"given":"Clara","family":"Pereira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0010-8607","authenticated-orcid":false,"given":"Vasco M.","family":"Barreto","sequence":"additional","affiliation":[]},{"given":"David M.","family":"Langenau","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4826-8976","authenticated-orcid":false,"given":"Jo\u00e3o T.","family":"Barata","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"1590_CR1","doi-asserted-by":"publisher","first-page":"3398","DOI":"10.1172\/JCI61269","volume":"122","author":"P Van Vlierberghe","year":"2012","unstructured":"Van Vlierberghe P, Ferrando A. 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