MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia

Exp Hematol. 2015 Oct;43(10):858-868.e7. doi: 10.1016/j.exphem.2015.05.018. Epub 2015 Jul 8.


A precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable prognosis, whereas patients with low miR-223 expression levels were associated with worse outcome. Furthermore, miR-223 was hierarchically expressed in AML subpopulations, with lower expression in leukemic stem cell-containing fractions. Genetic depletion of miR-223 decreased the leukemia initiating cell (LIC) frequency in a myelomonocytic AML mouse model, but it was not mandatory for rapid-onset AML. To relate these observations to physiologic myeloid differentiation, we knocked down or ectopically expressed miR-223 in cord-blood CD34⁺ cells using lentiviral vectors. Although miR-223 knockdown delayed myeloerythroid precursor differentiation in vitro, it increased myeloid progenitors in vivo following serial xenotransplantation. Ectopic miR-223 expression increased erythropoiesis, T lymphopoiesis, and early B lymphopoiesis in vivo. These findings broaden the role of miR-223 as a regulator of the expansion/differentiation equilibrium in hematopoietic stem and progenitor cells where its impact is dose- and differentiation-stage-dependent. This also explains the complex yet minor role of miR-223 in AML, a heterogeneous disease with variable degree of myeloid differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Proliferation / genetics
  • Erythropoiesis / genetics
  • Female
  • Fetal Blood / metabolism*
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Lymphopoiesis / genetics
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Middle Aged
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics


  • MIRN223 microRNA, human
  • MIRN223 microRNA, mouse
  • MicroRNAs
  • RNA, Neoplasm