Project description:Background: MLL-rearranged (MLLr) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) involve reciprocal oncogenic translocations of the KMT2A/KMT2B (MLL1/MLL2) gene on chromosome 11q23 with various translocation partner genes, which yields to chimeric MLL fusion proteins (MLL-FPs). Menin, the protein product of the MEN1 gene, is essential for the leukemogenic activity of MLL-FPs. Revumenib, a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, has recently received FDA approval for clinical use for the treatment of adult and pediatric patients with relapsed or refractory MLLr acute leukemia. Notably, menin also interacts with the AP-1 transcription factor JUND through a conserved sequence identical to that required for MLL-FP binding. Despite this structural similarity, the impact of menin-MLL inhibitors on JUND function has remained unexplored. Results: In this study, we investigated the influence of menin-MLL inhibitors on JUND activity. Quantitative mass spectrometry analysis of MLLr leukemia cells treated with menin-MLL inhibitors demonstrated that they also disrupt menin-JUND protein interactions. Furthermore, CRISPR-mediated inactivation of JUND or pharmacological inhibition using JNK inhibitors synergistically enhanced the anti-leukemic effects of menin-MLL inhibitors, leading to reduced cell proliferation, cell cycle arrest and apoptosis. RNA sequencing and chromatin binding assays revealed that menin-MLL inhibitor treatment increases JUND chromatin occupancy, leading to upregulation of target gene expression and potentially contributing to the development of resistance to menin-MLL inhibitors. Mouse models engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. Conclusion: These findings suggest that targeting JUND activity may significantly enhance the efficacy of menin-MLL inhibitors towards MLLr leukemia cells.

Project description:Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM. The reduced representation bisulfite sequencing (RRBS) approach (Meissner et al., 2008) was used to generate genome-wide single-base resolution CpG methylation profiles of three primary GBMs (1063T, 1133T, and 1142T) and three GSC lines (1063S, 1133S, 1142S) derived from these primary GBM tumors. The NSC line and the normal brain (NB) tissue sample were used as controls for comparison purposes. In addition, we analyzed three GBM xenograft tumor tissue samples (Mayo22, Mayo39, Mayo59) developed by Dr. Jann N. Sarkaria of Mayo Clinic.

			Action	DRS
	EO277.index	Other
	EO277.raw	Raw
	EO278.index	Other
	EO278.raw	Raw
	EO279.index	Other

Dataset Information

Epigenetic-focused CRISPR-Cas9 screen identifies ASH2L as a regulator of Glioblastoma cell survival

Dataset's files

Publications

Epigenetic-focused CRISPR/Cas9 screen identifies (absent, small, or homeotic)2-like protein (ASH2L) as a regulator of glioblastoma cell survival.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets