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Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis \u201cph-like\u201d BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34<jats:sup>+<\/jats:sup>hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD\/LtSz-<jats:italic>scid IL2R\u03b3<\/jats:italic><jats:sup><jats:italic>null<\/jats:italic><\/jats:sup>mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34<jats:sup>+<\/jats:sup>CD10<jats:sup>high<\/jats:sup>CD19<jats:sup>+<\/jats:sup>cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2\u2009A (<jats:italic>CDKN2A<\/jats:italic>) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of<jats:italic>CDKN2A<\/jats:italic>in primary human CD34<jats:sup>+<\/jats:sup>cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.<\/jats:p>","DOI":"10.1038\/s41467-022-28218-7","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T11:07:29Z","timestamp":1643886449000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["An instructive role for Interleukin-7 receptor \u03b1 in the development of human B-cell precursor leukemia"],"prefix":"10.1038","volume":"13","author":[{"given":"Ifat","family":"Geron","sequence":"first","affiliation":[]},{"given":"Angela Maria","family":"Savino","sequence":"additional","affiliation":[]},{"given":"Hila","family":"Fishman","sequence":"additional","affiliation":[]},{"given":"Noa","family":"Tal","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7463-3503","authenticated-orcid":false,"given":"John","family":"Brown","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1013-9490","authenticated-orcid":false,"given":"Virginia A.","family":"Turati","sequence":"additional","affiliation":[]},{"given":"Chela","family":"James","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3488-0248","authenticated-orcid":false,"given":"Jolanda","family":"Sarno","sequence":"additional","affiliation":[]},{"given":"Michal","family":"Hameiri-Grossman","sequence":"additional","affiliation":[]},{"given":"Yu Nee","family":"Lee","sequence":"additional","affiliation":[]},{"given":"Avigail","family":"Rein","sequence":"additional","affiliation":[]},{"given":"Hillary","family":"Maniriho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-1306","authenticated-orcid":false,"given":"Yehudit","family":"Birger","sequence":"additional","affiliation":[]},{"given":"Anna","family":"Zemlyansky","sequence":"additional","affiliation":[]},{"given":"Inna","family":"Muler","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7182-2592","authenticated-orcid":false,"given":"Kara L.","family":"Davis","sequence":"additional","affiliation":[]},{"given":"Victoria","family":"Marcu-Malina","sequence":"additional","affiliation":[]},{"given":"Nicole","family":"Mattson","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2714-9011","authenticated-orcid":false,"given":"Oren","family":"Parnas","sequence":"additional","affiliation":[]},{"given":"Rabea","family":"Wagener","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-2489","authenticated-orcid":false,"given":"Ute","family":"Fischer","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4826-8976","authenticated-orcid":false,"given":"Jo\u00e3o T.","family":"Barata","sequence":"additional","affiliation":[]},{"given":"Catriona H. 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