Abstract
SummaryPharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.
Highlights
Lysine-specific demethylase 1 (LSD1, known as KDM1A, AOF2, BHC110 or KIAA0601) is one of a number of epigenetic regulators that have recently emerged as candidate therapeutic targets in cancer
If the primary mechanism by which these compounds induce differentiation is through blockade of the histone demethylase activity of LSD1, it would be expected that changes in transcription due to LSD1 inhibition would be tightly correlated with co-localized increases in mono- and dimethyl histone H3K4 methylation, the modifications targeted for demethylation by LSD1
Among the most highly upregulated genes was CD86, which is induced during monocyte/macrophage differentiation (Lynch et al, 2013), and among the most highly downregulated was KIT, which is expressed by hematopoietic stem and progenitor cells (HSPCs) and downregulated during differentiation (Figure 1E; Table S2)
Summary
Lysine-specific demethylase 1 (LSD1, known as KDM1A, AOF2, BHC110 or KIAA0601) is one of a number of epigenetic regulators that have recently emerged as candidate therapeutic targets in cancer. It was initially identified as a core component of an RCOR1 (CoREST) histone deacetylase (HDAC) transcription corepressor complex (You et al, 2001) and later found to have lysine-specific demethylase activity (Shi et al, 2004). With regard to its enzymatic function, LSD1 is a flavin adenine dinucleotide (FAD)-dependent homolog of the amine oxidase family, with an ability to demethylate monomethyl or dimethyl lysine 4 (K4) of histone H3, releasing hydrogen peroxide and formaldehyde (Shi et al, 2004). LSD1 interacts with multiple transcription factors (Lynch et al, 2012), raising the possibility that other mechanisms may be significant
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