Lysine-specific demethylase 1A and Retinoic acid receptor alpha (LSD1 + RARα)

Lysine-specific demethylase 1A (LSD1/KDM1A) and Retinoic acid receptor alpha (RARα) constitute a critical regulatory axis in myeloid development and a significant therapeutic target pair in oncology. LSD1 is a flavin-dependent monoamine oxidase that demethylates histone H3 lysine 4 (H3K4me1/2), typically functioning as a co-repressor that maintains leukemia cells in an undifferentiated state (UniProt O60341). RARα is a nuclear receptor that, upon binding to retinoic acid, acts as a transcription factor to drive myeloid differentiation (UniProt P10276). In acute myeloid leukemia (AML), LSD1 often occupies RARα target gene promoters, creating a repressive epigenetic environment that blocks the pro-differentiative signals of retinoic acid. Therapeutic strategies involve using LSD1 inhibitors to "prime" the chromatin, making it accessible for RARα agonists like all-trans retinoic acid (ATRA) to trigger terminal differentiation of malignant blasts. This dual-targeting approach is particularly relevant for non-APL AML subtypes that are traditionally resistant to ATRA monotherapy. Clinical trials, such as those investigating the LSD1 inhibitor iadademstat in combination with ATRA, have demonstrated the potential of this axis to induce clinical responses in patients with relapsed or refractory AML (NCT02717884).

Other names

KDM1ALSD1RAR-alphaNR1B1AOF2BHC110Retinoic acid receptor alpha

LSD1 inhibition prevents the demethylation of H3K4me1/2 at RARα target gene promoters, disrupting the repressive chromatin state and sensitizing myeloid leukemia cells to RARα-mediated terminal differentiation induced by retinoic acid (Schenk et al., 2012, Nature Medicine).