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

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...

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Published in:Experimental hematology 2015-10, Vol.43 (10), p.858-868.e7
Main Authors: Gentner, Bernhard, Pochert, Nicole, Rouhi, Arefeh, Boccalatte, Francesco, Plati, Tiziana, Berg, Tobias, Sun, Su Ming, Mah, Sarah M, Mirkovic-Hösle, Milijana, Ruschmann, Jens, Muranyi, Andrew, Leierseder, Simon, Argiropoulos, Bob, Starczynowski, Daniel T, Karsan, Aly, Heuser, Michael, Hogge, Donna, Camargo, Fernando D, Engelhardt, Stefan, Döhner, Hartmut, Buske, Christian, Jongen-Lavrencic, Mojca, Naldini, Luigi, Humphries, R. Keith, Kuchenbauer, Florian
Format: Article
Language:English
Subjects:
Adult
Advanced Basic Science
Animals
Cell Proliferation - genetics
Erythropoiesis - genetics
Female
Fetal Blood - metabolism
Hematology, Oncology and Palliative Medicine
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
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Summary: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.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2015.05.018