202211Kawano

研究発表を行った学会；第81回日本癌学会学術総会
2022年9月29日-10月1日　（パシフィコ横浜）
タイトル； The mechanism of leukemia by gain-of-function mutation in miR-142.
発表者；河野　慎吾氏
（熊本大学　生命資源研究・支援センター　ゲノム機能分野）
要旨；
Mutations of MicroRNAs (miRNAs) are known to promote carcinogenesis. Point mutations of miRNA-142 (miR142) are observed in tumor cells of patients with acute myeloid leukemia (AML). To understand the role of miR142 mutation in AML, by utilizing a CRISPR/Cas9 system, we have successfully generated miR142 knockout (KO) mice and miR142-55A>G mutant knock-in (KI) mice, of which mutation is frequently observed among patients with miR142 mutated AML. We performed transplantation using bone marrow cells from miR142 KO and KI mice, and found that miR142 mutant KI cells develop CD8+ T cell leukemia four months or later post the transplantation, while miR142 KO cells did not. RNA-seq analysis in LSK stem progenitor cells and CD8+ T cells revealed that the miR142-KI cells specifically suppressed transcription of predicted target genes, which were involved pathways of apoptosis and T-cell differentiation. Because IDH2 mutations are often found in miR142 mutations in AML patients, we found miR142 KI/Idh2 mutant compound mice to develop AML. These data indicate gain-of-function of the miR142 mutation to drive leukemic transformation of hematopoietic stem cells.