Down regulation of NLK by MIR-221/222 modulates chemosensitivity to glucocorticoids in pediatric normal karyotype b-cell precursor acute lymphoblastic leukemia. La downregolazione di nemo-like kinase indotta dai MIR-221/222 modula chemiosensibilità ai glucocorticoidi nella pediatrico b-cell precursor leucemia linfattica acuta

Normal karyotype pediatric B-cell precursor ALL patients are heterogeneous with respect to chemotherapy response, relapse rates and prognosis and the reason is unknown. These patients are treated with a standard protocol, and stratified using MRD methodology that shows they have variable responses and predicted outcomes. This study aims to determine the reasons behind such heterogeneity. This study shows that through miRNA profiling, miR-221/222 are differentially expressed in normal karyotype patients and are up regulated in Poor Responder patients. Through proliferation, apoptosis, viability assays and cell cycle analysis, proliferation advantage was identified as the main cause of resistance to glucocorticoid treatment in miR-221/222 over expressing cell lines. SMAD1 and CREBBP were down regulated in miR-221/222 over expressing cell lines implicating the dysregulation of TGFβ and glucocorticoid-receptor pathways, while NLK was identified as a novel target of miR-221/222 through which resistance to chemotherapy is mediated.