Targeting the scaffolding role of LSD1(KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation [ChIP-seq]

The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors . In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells through degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knock-out, but LSD1 inhibition sensitizes them to physiological doses of RA without altering the stability of PML-RAR, and extends survival of leukemic mice upon RA treatment. Non-enzymatic activities of LSD1 are essential to block differentiation of leukemic cells, while the combination of LSD1 inhibitors (or LSD1 knock-out) with low doses of RA releases a differentiation-associated gene expression program, not strictly dependent on changes in histone H3K4 methylation (known substrate of LSD1). An integrated proteomic/epigenomic/mutational analysis showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin through inhibition of the interaction between LSD1 and GFI1, a relevant transcription factor in hematopoiesis. Overall design: H3K4me1, H3K4me2, H3K4me3 and H3K27ac ChIP-seq on NB4 cells treated with DMSO, MC_2580 (LSD1 inhibitor), RA 0.01 µM, RA 1µM and MC_2580 + RA 0.01µM. Series includes anti-LSD1 chIP on DMSO and MC_2580-treated NB4 cells and GFI1 ChIP-seq on untreated cells.