Knockout of both miR-15/16 loci induces acute myeloid leukemia

Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13069-13074. doi: 10.1073/pnas.1814980115. Epub 2018 Nov 26.

Abstract

MicroRNAs (miRNAs) have been extensively reported to be associated with hematological malignancies. The loss of miR-15a/16-1 at chromosome 13q14 is a hallmark of most of human chronic lymphocytic leukemia (CLL). Deletion of murine miR-15a/16-1 and miR-15b/16-2 has been demonstrated to promote B cell malignancies. Here, we evaluate the biological role of miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout mice. Unexpectedly, the complete deletion of both clusters promoted myeloproliferative disorders in the majority of the mice by the age of 5 months with a penetrance of 70%. These mice showed a significant enlargement of spleen and abnormal swelling of lymph nodes. Flow cytometry characterization demonstrated an expanded CD11b/Gr-1 double-positive myeloid population both in spleen and in bone marrow. The transplantation of splenocytes harvested from double-KO mice into wild-type recipient mice resulted in the development of myeloproliferative disorders, as observed in the donors. In vivo, miR-15/16 cluster deletion up-regulated the expression of Cyclin D1, Cyclin D2, and Bcl-2. Taken together, our findings identify a driver oncogenic role for miR-15/16 cluster deletion in different leukocytic cell lineages.

Keywords: acute myeloid leukemia; miR-15/16 cluster; mouse model.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cyclins / metabolism
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / physiology*
  • Spleen / metabolism
  • Spleen / pathology

Substances

  • Cyclins
  • MicroRNAs
  • Mirn15 microRNA, mouse
  • Mirn16 microRNA, mouse