ABSTRACT
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and the infiltration of leukemic cells is critical for disease progression and relapse. Nuclear deformability plays a critical role in cancer cell invasion through confined spaces; however, the direct impact of epigenetic changes on the nuclear deformability of leukemic cells remains unclear. Here, we characterized how 3D collagen matrix conditions induced H3K4 methylation in ALL cell lines and clinical samples. We used specific shRNA and chemical inhibitors to target WDR5 (a core subunit involved in H3K4 methylation) and determined that targeting WDR5 reduced the H3K4 methylation induced by the 3D environment and the invasiveness of ALL cells in vitro and in vivo. Intriguingly, targeting WDR5 did not reduce the adhesion or the chemotactic response of leukemia cells, suggesting a different mechanism by which H3K4 methylation might govern ALL cell invasiveness. Finally, we conducted biochemical, and biophysical experiments to determine that 3D environments promoted the alteration of the chromatin, the morphology, and the mechanical behavior of the nucleus in ALL cells. Collectively, our data suggest that 3D environments control an upregulation of H3K4 methylation in ALL cells, and targeting WDR5 might serve as a promising therapeutic target against ALL invasiveness in vivo.
Subject(s)
Histones , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Histones/metabolism , Methylation , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Epigenesis, Genetic , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolismABSTRACT
Efficient exfoliation of graphene and related materials (GRM) and fast and inexpensive integration/assembly are crucial to fulfil their full potential. A high degree of exfoliation in organic media can be achieved with high boiling point liquids that usually leave residues after drying, which is a handicap for many applications. Here, the effective exfoliation and dispersion of GRM in a vinyl monomer, which is subsequently converted to a functional polymer by photopolymerization, is reported. Nanocomposite membranes and three-dimensional objects are produced by the photo-curing process and stereolithography 3D printing, respectively.
