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We developed a <jats:italic>Gata1<\/jats:italic> knock-down allele (<jats:italic>Gata1.05<\/jats:italic>) that results in GATA1 expression at 5% of endogenous level. In female mice heterozygous for both the <jats:italic>Gata1.05<\/jats:italic> and wild-type alleles, we observed a predisposition to erythroblastic leukemia three to six months after birth. Since no male <jats:italic>Gata1.05<\/jats:italic> progeny survive gestation, we originally maintained heterozygous females in a mixed genetic background of C57BL\/6J and DBA\/2 strains. Around 30% of these mice reproducibly develop leukemia, but the other subset did not develop leukemia, even though they harbor a high number of preleukemic erythroblasts. These observations prompted us to hypothesize that there may be potential influence of genetic determinants on the progression of <jats:italic>Gata1.05<\/jats:italic>-driven hematopoietic precursors to full-blown leukemia. In an initial examination of <jats:italic>Gata1.05<\/jats:italic>\/X mice backcrossed into C3H\/He, BALB\/c, DBA\/2, C57BL\/6J and 129X1\/SvJ strains, we discerned that the backgrounds of C57BL\/6J and 129X1\/SvJ significantly expedited leukemia onset in <jats:italic>Gata1.05<\/jats:italic>\/X mice. Conversely, backgrounds of C3H\/He, BALB\/c and DBA\/2 did not substantially modify the effect of the <jats:italic>Gata1<\/jats:italic> mutation. This indicates the existence of genetic modifiers that accentuate <jats:italic>Gata1.05<\/jats:italic> leukemogenesis. Subsequent cohort studies evaluated <jats:italic>Gata1.05<\/jats:italic>\/X mice within mix backgrounds of BALB\/c:129X1\/SvJ and BALB\/c:C57BL\/6J. In these settings, <jats:italic>Gata1.05<\/jats:italic>-driven leukemia manifested in autosomal dominant patterns within the 129X1\/SvJ background and in autosomal recessive patterns within C57BL\/6J background. To the best of our knowledge, this study provides the inaugural evidence of genetic modifiers that can reshape the outcome based on leukemia-associated gene signatures.<\/jats:p>","DOI":"10.1186\/s40164-024-00491-w","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T07:02:14Z","timestamp":1708930934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Strain-dependent modifiers exacerbate familial leukemia caused by GATA1-deficiency"],"prefix":"10.1186","volume":"13","author":[{"given":"Ikuo","family":"Hirano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanako","family":"Abe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James Douglas","family":"Engel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ritsuko","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"491_CR1","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1101\/gad.4.10.1650","volume":"4","author":"M Yamamoto","year":"1990","unstructured":"Yamamoto M, Ko LJ, Leonard MW, Beug H, Orkin SH, Engel JD. Activity and tissue-specific expression of the transcription factor NF-E1 multigene family. Genes Dev. 1990;4:1650\u201362.","journal-title":"Genes Dev"},{"key":"491_CR2","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1084\/jem.20020170","volume":"195","author":"R Hirasawa","year":"2002","unstructured":"Hirasawa R, Shimizu R, Takahashi S, et al. Essential and instructive roles of GATA factors in eosinophil development. J Exp Med. 2002;195:1379\u201313.","journal-title":"J Exp Med"},{"key":"491_CR3","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1084\/jem.20021149","volume":"197","author":"AR Migliaccio","year":"2003","unstructured":"Migliaccio AR, Rana RA, Sanchez M, et al. GATA-1 as a regulator of mast cell differentiation revealed by the phenotype of the GATA-1low mouse mutant. J Exp Med. 2003;197:281\u201396.","journal-title":"J Exp Med"},{"key":"491_CR4","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.exphem.2016.05.010","volume":"44","author":"R Shimizu","year":"2016","unstructured":"Shimizu R, Yamamoto M. GATA-related hematologic disorders. Exp Hematol. 2016;44:696\u2013705.","journal-title":"Exp Hematol"},{"key":"491_CR5","doi-asserted-by":"publisher","first-page":"12611","DOI":"10.1074\/jbc.272.19.12611","volume":"272","author":"S Takahashi","year":"1997","unstructured":"Takahashi S, Onodera K, Motohashi H, et al. Arrest in primitive erythroid cell development caused by promoter-specific disruption of the GATA-1 gene. J Biol Chem. 1997;272:12611\u20135.","journal-title":"J Biol Chem"},{"key":"491_CR6","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1128\/MCB.24.24.10814-10825.2004","volume":"24","author":"R Shimizu","year":"2004","unstructured":"Shimizu R, Kuroha T, Ohneda O, et al. Leukemogenesis caused by incapacitated GATA-1 function. Mol Cell Biol. 2004;24:14\u20130825.","journal-title":"Mol Cell Biol"},{"key":"491_CR7","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1074\/jbc.M500081200","volume":"280","author":"X Pan","year":"2005","unstructured":"Pan X, Ohneda O, Ohneda K, et al. Graded levels of GATA-1 expression modulate survival, proliferation, and differentiation of erythroid progenitors. J Biol Chem. 2005;280:85\u201322394.","journal-title":"J Biol Chem"},{"key":"491_CR8","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/nrc2348","volume":"8","author":"R Shimizu","year":"2008","unstructured":"Shimizu R, Engel JD, Yamamoto M. GATA1-related leukaemias. 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Am J Hematol. 2017;92:292\u20136.","journal-title":"Am J Hematol"}],"container-title":["Experimental Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-024-00491-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40164-024-00491-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-024-00491-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T22:13:17Z","timestamp":1709244797000},"score":1,"resource":{"primary":{"URL":"https:\/\/ehoonline.biomedcentral.com\/articles\/10.1186\/s40164-024-00491-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":10,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["491"],"URL":"https:\/\/doi.org\/10.1186\/s40164-024-00491-w","relation":{},"ISSN":["2162-3619"],"issn-type":[{"type":"electronic","value":"2162-3619"}],"subject":[],"published":{"date-parts":[[2024,2,26]]},"assertion":[{"value":"15 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal studies were conducted in accordance with guidelines approved by the Institutional Animal Experiment Committee of the Tohoku University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participant"}},{"value":"All authors approved the manuscript and the submission.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23"}}