Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid–induced differentiation

Abstract

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, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

IGFBP7 activates retinoid acid–induced responses in acute myeloid leukemia stem and progenitor cells

“…51 Combined treatment using LSD1 inhibitors and retinoic acids allows differentiation and growth arrest of APL cells without affecting the stability of PML-RARa and its recruitment to chromatin. 27 In primary non-APL, rhIGFBP7 treatment reduced GFI1 and led to increased sensitivity for ATRA-induced responses. GFI1 is a transcriptional repressor interacting with the REST corepressor 1 (CoREST) complex and LSD1 to regulate gene expression and inhibit p53 activity, and depletion of LSD1 enhances transcription of GFI1 targets.…”

“…55 Inhibitors of LSD1 disrupt the interaction between LSD1 with GFI1, thereby targeting the GFI1/ CoREST complex for disruption and release from the chromatin. 27,29 Because disruption of this complex is required for leukemia cells to differentiate, 29 rhIGFBP7 is expected to reduce GFI1 levels, leading to fewer GFI1 complexes on the chromatin and enhanced sensitivity for ATRA-induced differentiation. Pharmacological inhibition of LSD1 mimics depletion of GFI1, 27 and activation of ATRA-driven responses by rhIGFBP7 might mimic LSD1 inhibition by reducing GFI1.…”

“…27,29 Because disruption of this complex is required for leukemia cells to differentiate, 29 rhIGFBP7 is expected to reduce GFI1 levels, leading to fewer GFI1 complexes on the chromatin and enhanced sensitivity for ATRA-induced differentiation. Pharmacological inhibition of LSD1 mimics depletion of GFI1, 27 and activation of ATRA-driven responses by rhIGFBP7 might mimic LSD1 inhibition by reducing GFI1. LSD1 interacts with the chromatin, in different cell types, through distinct complexes of epigenetic modifiers and transcription factors, 56 and inhibition of LSD1 was demonstrated to interfere with GFI1-mediated repression of PU.1 target gene expression.…”

“…24,26,27 LSD1 interacts with growth factor independent 1 (GFI1), and the activity of LSD1 is dependent on this interaction. [27][28][29] Multiple distinct LSD1 inhibitors disrupt the interaction of LSD1 with GFI1, destabilizing GFI1 on chromatin and abrogating its repressive activity. The subsequent activation of enhancers following disruption of the GFI1 repressor complex is believed to be dependent on the presence of SPI1 and CEBPa at GFI1-bound loci.…”

LSD1: more than demethylation of histone lysine residues

“…Finally, different groups have demonstrated that LSD1 scaffold activity, dynamically involved in carcinogenesis [149][150][151][152] , may be critical for unsuccessful therapies based on its catalytic inhibition in some cancers 152,153 . In particular, in AML cells resistant to LSD1 catalytic inhibition, the protein primarily represents a scaffold that recruits the CoREST complex to inhibit cell differentiation; in fact, inhibitors of LSD1 demethylase-independent activity induce the dissociation of the complex and responses to differentiation stimuli (such as RA) 150 .…”