Abstract
AbstractDeregulated expression of microRNAs is associated with neoplasia. Here, we show that mature miR-16 levels are abnormally increased in CD34+ cells of patients with polycythemia vera as a consequence of preferential expression of miR-16-2 on chromosome 3 rather than of miR-16-1 on chromosome 13. Forced expression of miRNA-16 in normal CD34+ cells stimulated erythroid cell proliferation and maturation. Conversely, exposure of polycythemia vera CD34+ cells to small interfering RNA against pre-miR-16-2 reduced erythroid colonies and largely prevented formation of erythropoietin-independent colonies; myeloid progenitors remained unaffected. Experiments with knock down of JAK2 indicated that overexpression of miR-16 was independent of JAK/STAT pathway activation. Mice injected with an miR-16 antagomir showed a blunted erythroid response to exogenous erythropoietin, which indicates a role of miR-16 in normal erythropoiesis. These data suggest that deregulation of miR-16-2 contributes to abnormal expansion of erythroid lineage in polycythemia vera. However, the mechanisms for miR-16-2 overexpression remain to be elucidated, because no genetic abnormalities at the miR-16-2 locus were discovered.
Highlights
MicroRNAs are small noncoding RNAs that intervene in the regulation of cell proliferation, differentiation, and apoptosis by silencing target genes.[1]
The myeloproliferative neoplasms polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis (PMF) originate from deregulated proliferation of hematopoietic stem cells, which leads to overproduction of mature blood cells.[7]
While studying the miRNA expression profile in PV CD34ϩ cells induced to erythroid differentiation, we observed that expression of miR-16 remained steadily high over time, unlike in normal cells, in which a prompt decline after culture initiation was followed by a late increase at day 9-12 coincident with erythroblast generation (Figure 1A).[10,12,17]
Summary
MicroRNAs (miRNAs) are small noncoding RNAs that intervene in the regulation of cell proliferation, differentiation, and apoptosis by silencing target genes.[1]. While studying the miRNA expression profile in PV CD34ϩ cells induced to erythroid differentiation, we observed that expression of miR-16 remained steadily high over time, unlike in normal cells, in which a prompt decline after culture initiation was followed by a late increase at day 9-12 coincident with erythroblast generation (Figure 1A).[10,12,17] we postulated that miR-16 deregulation could contribute to abnormal erythropoiesis in PV.
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