Ablation of miR-146b in mice causes hematopoietic malignancy

Abstract

Excessive and constitutive activation of nuclear factor-kB (NF-kB) 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-kB 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 generatedmiR-146b-knockout (KO) and miR-146a-KO mice by genome editing and found that both strains developed hematopoieticmalignancies such as B-cell lymphoma and acutemyeloid 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-kB activity. Consistent with these findings, bothmiR-146a- and miR-146b-KO B cells showed a high proliferative capacity. Taken together, sustained NF-kB activation in miR-146b KO mice could lead to the development of hematopoietic malignancy with aging.