Abstract
Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ hematopoietic progenitor cells (HPCs), in order to elucidate its role in PMF pathogenesis here we unravelled the effects of miR-34a-5p overexpression in HPCs. We showed that enforced expression of miR-34a-5p partially constrains proliferation and favours the megakaryocyte and monocyte/macrophage commitment of HPCs. Interestingly, we identified lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts as miR-34a-5p-targets downregulated after miR-34a-5p overexpression in HPCs as well as in PMF CD34+ cells. Remarkably, the knockdown of NR4A2 in HPCs mimicked the antiproliferative effects of miR-34a-5p overexpression, while the silencing of LEF1 phenocopied the effects of miR-34a-5p overexpression on HPCs lineage choice, by favouring the megakaryocyte and monocyte/macrophage commitment. Collectively our data unravel the role of miR-34a-5p in HPCs fate decision and suggest that the increased expression of miR-34a-5p in PMF HPCs could be important for the skewing of megakaryopoiesis and the production of monocytes, that are key players in BM fibrosis in PMF patients.
Highlights
Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph−) myeloproliferative neoplasm (MPN)
We demonstrated that the effects of miR-34a-5p overexpression on the hematopoietic progenitor cells (HPCs) proliferation and fate decision are mediated by the downregulation of its targets lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2)
Since janus kinase 2 (JAK2), MPL and CALR mutations all converge toward the constitutive activation of JAK/STAT pathway, our data suggest that the deranged JAK/STAT signaling could underlie the upregulation of miR-34a-5p in PMF CD34+ cells
Summary
Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph−) myeloproliferative neoplasm (MPN). The presence of hyperplastic and dysplastic megakaryocytes and the detection of fibrosis in the BM are the main criteria for differential diagnosis of PMF from ET and PV, according to the World Health Organization (WHO) classification of Ph− MPNs [1,3]. The aberrantly differentiated megakaryocytes which accumulate in the BM play a major role in the release of proinflammatory and profibrotic cytokines, chemokines and growth factors that in turn drive the development of BM fibrosis, osteosclerosis and eventually extramedullary hematopoiesis in PMF patients. Monocytes are involved in the overproduction of proinflammatory and profibrotic mediators that fuel the development of fibrosis and other alterations of the BM architecture in PMF patients [4,5,6,7]
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