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

Francesca Lovat1,2, Matteo Fassan3, Diana Sacchi3

  • 1Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210.

Proceedings of the National Academy of Sciences of the United States of America
|November 28, 2018
PubMed

Insights

Complete deletion of miR-15/16 gene clusters unexpectedly drives myeloproliferative disorders in mice, revealing a novel oncogenic role for these microRNAs in leukocytic cell lineages.

Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • MicroRNAs (miRNAs) are implicated in hematological malignancies.
  • Loss of miR-15a/16-1 at chromosome 13q14 is characteristic of chronic lymphocytic leukemia (CLL).
  • Previous studies linked murine miR-15a/16-1 and miR-15b/16-2 deletion to B cell malignancies.

Purpose of the Study:

  • To investigate the biological role of the miR-15/16 gene clusters.
  • To determine the consequences of complete deletion of both miR-15a/16-1 and miR-15b/16-2 clusters.

Main Methods:

  • Crossbreeding of miR-15a/16-1 and miR-15b/16-2 knockout mice.
  • Phenotypic analysis including spleen and lymph node assessment.
  • Flow cytometry to characterize myeloid populations.
  • Splenocyte transplantation into wild-type recipient mice.

Main Results:

  • Complete deletion of both miR-15/16 clusters led to myeloproliferative disorders in 70% of mice by 5 months.
  • Affected mice exhibited enlarged spleens and swollen lymph nodes.
  • Expanded CD11b/Gr-1 positive myeloid populations were observed in spleen and bone marrow.
  • Transplantation of splenocytes from double-KO mice induced myeloproliferative disorders in recipients.
  • In vivo, miR-15/16 cluster deletion upregulated Cyclin D1, Cyclin D2, and Bcl-2 expression.

Conclusions:

  • The miR-15/16 gene clusters play a critical role in preventing myeloproliferative disorders.
  • Deletion of miR-15/16 clusters has a driver oncogenic role in various leukocytic cell lineages.
  • These findings uncover a novel function of miR-15/16 in myeloid malignancies.
Keywords:
acute myeloid leukemiamiR-15/16 clustermouse model

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