ABSTRACT
The hematological malignancies classified as mixed lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis, and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia, here we show that genetic inactivation or small-molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein-driven transformation. Genome-wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small-molecule inhibitors in the treatment of leukemias harboring MLL rearrangements.
Subject(s)
Antineoplastic Agents/pharmacology , Histone-Lysine N-Methyltransferase/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Cell Line, Tumor , Disease Models, Animal , Gene Deletion , Gene Expression Regulation, Leukemic/drug effects , Gene Expression Regulation, Leukemic/genetics , Gene Rearrangement/drug effects , Gene Rearrangement/genetics , Mice , Mice, Inbred NOD , Mice, SCID , Oncogene Proteins, Fusion/geneticsABSTRACT
Radon monitoring at different levels of the cover of the Urgeiriça tailings shows that the sealing is effective and performing as desired in terms of containing the strongly radioactive waste resulting from uranium ore processing. However, the analysis of the time series of radon concentration shows a very complex temporal structure, particularly at depth, including very large and fast variations from a few tens of kBq m(-3) to more than a million kBq m(-3) in less than one day. The diurnal variability is strongly asymmetric, peaking at 18 h/19 h and decreasing very fast around 21 h/22 h. The analysis is performed for summer and for a period with no rain in order to avoid the potential influence of precipitation and related environmental conditions on the radon variability. Analysis of ancillary measurements of temperature, relative humidity, wind speed and wind direction, as well as atmospheric pressure reanalysis data shows that the daily averaged radon concentration in the taillings material is anti-correlated with the atmospheric pressure and that the diurnal amplitude is associated with the magnitude of atmospheric pressure daily oscillations.
