Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia

ABSTRACT

Introduction: Epigenetic dysregulation plays a critical role in the pathogenesis of acute myeloid leukemia (AML). Alterations in histone methylation lead to aberrant silencing of expression of multiple genes involved in tumor suppression and cell cycling, resulting in myeloid maturation arrest and proliferation of early myeloid progenitors. One promising approach targeting chromatin regulatory proteins is inhibition of lysine specific demethylase-1 (LSD1), an enzyme responsible for demethylation of histone H3 as well as other functions

Areas covered: Available literature on LSD1 in normal and malignant hematopoiesis was identified in PubMed and reviewed. Areas addressed here include the biology of LSD1, pharmacologic inhibitors, and preclinical data supporting the rationale for LSD1 inhibition in AML therapy.

Expert opinion: LSD1 inhibitors represent a promising novel epigenetic approach for AML therapy. Preclinical studies have revealed that pharmacologic LD1 inhibitors function primarily by altering stem cell programs and restoring myeloid differentiation to AML cells. These effects are markedly enhanced in combination with trans-retinoic acid or histone deacetylase inhibitors with little toxicity. Currently, multiple oral LSD1 inhibitors are undergoing phase 1 investigation in patients with AML. The results of these clinical trials are eagerly awaited.

KEYWORDS:

• Acute myeloid leukemia
• epigenetics
• lysine specific demethylase
• LSD1
• tranylcypromine analogues

Article highlights

• LSD1 is an FAD-dependent amine oxidase.

• LSD1 removes 1-2 methyl groups from lysine on histone H3 (H3K4 or H3K9).

• LSD1 acts as both a transcriptional repressor and activator in different contexts.

• LSD1 is overexpressed in myeloid malignancies, specifically acute myeloid leukemia.

• Potent pharmacologic inhibitors of LSD1 have been developed.

• LSD1 inhibitors exert promising anti-tumor activity in preclinical models of acute myeloid leukemia.

This box summarizes key points contained in the article.

Declaration of interest

E Wang is on the speaker’s bureau for Incyte and has received research funding from ImmunoGen Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.