Ablation of miR-146b in mice causes hematopoietic malignancy

• DOI: 10.1182/bloodadvances.2018017954
• Publication Date: 2018-12-07T16:45:17Z
• Authors: Takahiro Mitsumura; Yoshiaki Ito; Tomoki Chiba; Takahide Matsushima; Ryota Kurimoto; Yoko Tanaka; Tomomi Kato; Keisuke Uchida; Takashi Ito; Kouhei Yamamoto; Yoshinobu Eishi; Masanobu Kitagawa; Yasunari Miyazaki; Naohiko Inase; Hiroshi Asahara
• Keywords: Gene Editing; Lipopolysaccharides; Mice, Knockout; 0301 basic medicine; Aging; B-Lymphocytes; NF-kappa B; Antagomirs; Up-Regulation; Mice, Inbred C57BL; Mice; MicroRNAs; 03 medical and health sciences; Hematologic Neoplasms; Animals

Abstract Excessive and constitutive activation of nuclear factor-κB (NF-κB) leads to abnormal cell proliferation and differentiation, leading to the development of malignant tumors, including lymphoma. MicroRNA 146a (miR-146a) and miR-146b, both of which carry an identical seed sequence, have been shown to contribute to inflammatory diseases and tumors by suppressing the expression of key molecules required for NF-κB activation. However, the functional and physiological differences between miR-146a and miR-146b in disease onset have not been fully elucidated. In this study, we generated miR-146b–knockout (KO) and miR-146a–KO mice by genome editing and found that both strains developed hematopoietic malignancies such as B-cell lymphoma and acute myeloid leukemia during aging. However, the B-cell lymphomas observed in miR-146a– and miR-146b–KO mice were histologically different in their morphology, and the malignancy rate is lower in miR-146b mice than miR-146a mice. Upon mitogenic stimulation, the expression of miR-146a and miR-146b was increased, but miR-146b expression was lower than that of miR-146a. Using a previously developed screening system for microRNA targets, we observed that miR-146a and miR-146b could target the same mRNAs, including TRAF6, and inhibit subsequent NF-κB activity. Consistent with these findings, both miR-146a– and miR-146b–KO B cells showed a high proliferative capacity. Taken together, sustained NF-κB activation in miR-146b KO mice could lead to the development of hematopoietic malignancy with aging.