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MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR\u2010142) is frequently mutated in patients with follicular lymphoma, diffuse large B\u2010cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia\/myelodysplastic syndrome (AML\/MDS). To understand the role of miR\u2010142 mutation in blood cancers, the CRISPR\u2010Cas9 system was utilized to successfully generate miR\u2010142\u201055A&gt;G mutant knock\u2010in (Ki) mice, simulating the most frequent mutation in patients with miR\u2010142 mutated AML\/MDS. Bone marrow cells from miR\u2010142 mutant heterozygous Ki mice were transplanted, and we found that the miR\u2010142 mutant\/wild\u2010type cells were sufficient for the development of CD8<jats:sup>+<\/jats:sup> T\u2010cell leukemia in mice post\u2010transplantation. RNA\u2010sequencing analysis in hematopoietic stem\/progenitor cells and CD8<jats:sup>+<\/jats:sup> T\u2010cells revealed that miR\u2010142\u2010Ki\/+ cells had increased expression of the mTORC1 activator, a potential target of wild\u2010type miR\u2010142\u20103p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt\u2013mTOR pathway was suppressed in miR\u2010142\u201055A&gt;G heterozygous cells, indicating that these genes are repressed by the mutant miR\u2010142\u20103p. Thus, in addition to the loss of function due to the halving of wild\u2010type miR\u2010142\u20103p alleles, mutated miR\u2010142\u20103p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.<\/jats:p>","DOI":"10.1111\/cas.15794","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T04:44:06Z","timestamp":1679460246000},"page":"2821-2834","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A gain\u2010of\u2010function mutation in <scp>microRNA<\/scp> 142 is sufficient to cause the development of T\u2010cell leukemia in mice"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3765-2294","authenticated-orcid":false,"given":"Shingo","family":"Kawano","sequence":"first","affiliation":[{"name":"Institute of Resource Development and Analysis Kumamoto University  Kumamoto 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