What question did this study set out to answer?

This study aims to understand how acute myeloid leukemias respond to LSD1 inhibitors and identify molecular mechanisms involved.

May 15, 2026Open Access

KIT-dependent acute myeloid leukemias are responsive to LSD1 inhibition

AAAmal Kamal Abdel‐AzizAin Shams University MSMona Kamal SaadeldinSam Houston State University

Key Points

This study aims to understand how acute myeloid leukemias respond to LSD1 inhibitors and identify molecular mechanisms involved.
Conducted genome-wide transcriptomic profiling and RT-qPCR to assess gene expression.
Performed immunoblot analyses to evaluate protein levels of key targets.
Utilized chromatin immunoprecipitation to study LSD1 binding to KIT transcription start site.
KIT is overexpressed in LSD1i-sensitive AMLs compared to tolerant ones (p<0.05).
Inhibiting c-KIT enhanced the effect of LSD1 inhibitors (detailed metrics not provided).
Primary human AML samples showed a positive correlation between KIT and LSD1 transcript levels.

Abstract

Abstract Lysine specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent histone demethylase which is overexpressed in acute myeloid leukemias (AMLs). Indeed, several selective LSD1 inhibitors (LSD1is) are currently evaluated in clinical trials. We previously demonstrated that the mammalian target of rapamycin (mTOR) signalling is inhibited in LSD1i-sensitive AMLs and is activated in LSD1i-partially responsive/tolerant AMLs following LSD1i. Herein, we sought to systematically decipher the molecular basis underlying the responsiveness of AML cells to LSD1is. Genome-wide transcriptomic profiling, RT-qPCR and immunoblot analyses revealed that stem cell factor tyrosine kinase receptor (KIT) is preferentially overexpressed in LSD1i-sensitive AMLs compared to LSD1i-partially responsive/tolerant AMLs. Pharmacological and genetic interference with LSD1 repressed KIT transcription. c-Kit acted upstream of ERK/mTOR signalling. Chromatin immunoprecipitation studies revealed that LSD1 binds in proximity to KIT TSS and modulates repressive H3K9me2 marks. Inhibiting c-Kit augmented the anti-leukemic activity of LSD1is in KIT-dependent AML cells. Consistently, KIT mRNA positively correlated with LSD1 transcript levels in primary human AML biospecimens and pharmacological LSD1i repressed KIT transcription in primary human AML samples ex vivo . Collectively, this study sheds light on the epigenetic modulation of KIT transcription by LSD1 and underscores the therapeutic potential of co-targeting LSD1/KIT in KIT-dependent AMLs. Graphical Abstract

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