Ablation of miR-146b in mice causes hematopoietic malignancy

Blood Adv. 2018 Dec 11;2(23):3483-3491. doi: 10.1182/bloodadvances.2018017954.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Antagomirs / metabolism
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Gene Editing
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / pathology*
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • NF-kappa B / metabolism
  • Up-Regulation / drug effects


  • Antagomirs
  • Lipopolysaccharides
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • NF-kappa B