miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets.
BCR-ABL negative myeloproliferative neoplasms (MPNs; polycythemia vera, essential thrombocythemia, primary myelofibrosis) are malignant diseases arising from a multipotent hematopoietic progenitor, frequently altered by JAK2 V617F or other JAK/STAT activating mutations. The thrombopoietin receptor (TpoR, MPL) is one of the major dimeric cytokine receptors that use JAK2 in the myeloid lineage, and was found to be down-modulated in certain MPN patients. We searched for negative regulators of MPL expression. Here we report that miR-28 targets the 3' untranslated (3'UTR) region of MPL, inhibiting its translation, as well as other proteins potentially involved in megakaryocyte differentiation, such as E2F6. Expression of miR-28 in CD34-derived megakaryocytes inhibited terminal differentiation. miR-28 was found to be overexpressed in platelets of a fraction of MPN patients, while it was expressed at constant low levels in platelets from healthy subjects. Constitutive activation of STAT5 leading to autonomous growth of hematopoietic cell lines was associated with increased miR-28 expression. We discuss how down-modulating MPL and other targets of miR-28, and of related miR-708 and miR-151, could contribute to MPN pathogenicity.
Girardot
Michael
M
Ludwig Institute for Cancer Research Ltd, Brussels, Belgium.
Pecquet
Christian
C
Boukour
Siham
S
Knoops
Laurent
L
Ferrant
Augustin
A
Vainchenker
William
W
Giraudier
Stéphane
S
Constantinescu
Stefan N
SN
D020413:3' Untranslated Regions; D019943:Amino Acid Substitution; D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D055016:Megakaryocyte Progenitor Cells / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000097:blood / Q000209:etiology / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D050799:STAT5 Transcription Factor / Q000378:metabolism
D020413:3' Untranslated Regions; D017931:DNA Primers; D035683:MicroRNAs; D012333:RNA, Messenger; D053628:Receptors, Thrombopoietin; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2