miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

Abstract

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAK V617F mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK2 V617F inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-543 was significantly upregulated in nonresponders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2 V617F mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options.

Editing and Chemical Modifications on Non-Coding RNAs in Cancer: A New Tale with Clinical Significance

“…For example, we observed in different physiological/pathological situations very high correlations between the expressions of miRNAs from different patient samples and we translated these correlations into miRNA networks [ 175 , 176 , 177 , 178 ]. Initially, we discovered in sepsis that the correlations between circulating plasma miRNAs disappear, the miRNA network is fragmented, and many miRNA nodes are isolated in comparison to the miRNA network of healthy controls.…”

The Interplay between MicroRNAs and the Components of the Tumor Microenvironment in B-Cell Malignancies

“…MicroRNAs (miRNAs), a type of ncRNA, are considered one of the most potent epigenetic modulators [27,28]. MiRNAs function as major posttranscriptional gene regulators with critical roles in different cellular processes, such as differentiation, development, growth, angiogenesis, and apoptosis [29][30][31][32][33]. The ability of each miRNA to regulate several target genes simultaneously (more than 100 target genes) allows them to control multiple signaling pathways [34,35].…”

The role of miR‐543 in human cancerous and noncancerous diseases

“…LncRNA PVT1 specifically silenced miR‐543 in rheumatoid arthritis, and miR‐543 negatively regulated signal peptide‐CUB‐EGF‐like containing protein 2 (SCUBE2) expression, thereby inhibiting proliferation and interleukin‐1β (IL‐1β) secretion, while promoting apoptosis of fibroblast‐like synoviocytes (J. Wang, Kong, et al, 2020). And miR‐543 targets the dioxygenases ten‐eleven translocation 1 (TET1) and 2 (TET2) in myelofibrosis models, upregulation of miR‐543 promotes the expression of genes related to drug metabolism, including CYP3A4 (Fuentes‐Mattei et al, 2020). Keloids are benign fibroproliferative dermal tumors.…”