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

Bernhard Gentner, Nicole Pochert, Arefeh Rouhi, Francesco Boccalatte, Tiziana Plati, Tobias Berg, Su Ming Sun, Sarah M. Mah, Milijana Mirkovic-Hösle, Jens Ruschmann, Andrew Muranyi, Simon Leierseder, Bob Argiropoulos, Daniel T. Starczynowski, Aly Karsan, Michael Heuser, Donna Hogge, Fernando D. Camargo, Stefan Engelhardt, Hartmut DöhnerChristian Buske, Mojca Jongen-Lavrencic, Luigi Naldini, R. Keith Humphries, Florian Kuchenbauer

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)858-868
Number of pages11
JournalExperimental Hematology
Volume43
Issue number10
DOIs
Publication statusPublished - Oct 1 2015

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ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology
  • Medicine(all)

Cite this

Gentner, B., Pochert, N., Rouhi, A., Boccalatte, F., Plati, T., Berg, T., Sun, S. M., Mah, S. M., Mirkovic-Hösle, M., Ruschmann, J., Muranyi, A., Leierseder, S., Argiropoulos, B., Starczynowski, D. T., Karsan, A., Heuser, M., Hogge, D., Camargo, F. D., Engelhardt, S., ... Kuchenbauer, F. (2015). MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia. Experimental Hematology, 43(10), 858-868. https://doi.org/10.1016/j.exphem.2015.05.018