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- Histone demethylase KDM4C prevents cellular senescence in JAK2-mutated neoplasms
Histone demethylase KDM4C prevents cellular senescence in JAK2-mutated neoplasms
in: Oncology Research and Treatment (2022)
Background: JAK2 V617F mutations are associated with myeloproliferative neoplasms (MPN). Current therapeutic options are ineffective to eradicate JAK2-mutated clones. Hence, MPN patients are at risk of progressing to secondary acute myeloid leukemia. We sought to determine genetic vulnerabilities that may prevent persistence and progression of JAK2-mutated clones. Methods: Genome-scale lentiviral CRISPR-Cas9 screen. Proliferation and cell growth competition assay. Transcriptome analysis using RNAsequencing. Senescence screen using SA-sGal assay, laser scanning microscopy and Western blot. In vivo KDM4C CRISPR-Cas9 knockout using NXG Mouse Xenograft. Result: Using genome-scale CRISPR-Cas9 screen KDM4C showed dependence in HEL cells irrespective of co-treatment with Ruxolitinib. Genetic deletion of KDM4C in human and murine JAK2-mutated cells led to significant loss of proliferative advantage compared to non-deleted controls. Transcriptome analyses on HEL cells following KDM4C-deletion showed significant deregulation of senescence associated genes. GSEA revealed also enriched PI3K/AKT/mTOR and NF-κB signaling. A significant increase in SA-sGal and p21 expression was detected. NXG mice with JAK2-mutated leukemia and KDM4C-KO showed significantly improved survival compared to non-targeting controls. Discussion: Upon treatment with Ruxolitinib, JAK2-mutated cells survived depending on KDM4C expression. In vivo models of AML have shown delayed disease development following deletion of KDM4C. The evasion of senescence by KDM4C in JAK2-mutated cells observed here has been described so far in melanocytic cells, and its loss was also associated with loss of H3K9me3. Conclusion: JAK2-mutated cells are dependent on KDM4C activity irrespective to JAK-inhibitor treatment. Inhibition of KDM4C results in a proliferative disadvantage of JAK2-mutant cells, which can be explained by induction of cellular senescence. Sequential therapy combining KDM4C inactivation and senolysis may represent a promising therapeutic approach for JAK2-mutated MPN.
DOI: Array