Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia

By T. Schenk, W. Chen, S. Göllner, L. Howell, Liqing Jin, Katja Hebestreit, H. Klein, A. Popescu, A. Burnett, K. Mills and 10 more. Nature Medicine, 2012

623 citations recorded by the source corpus.

Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4me2) across the genome, but it did increase H3K4me2 and expression of myeloid-differentiation–associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID γ (with interleukin-2 (IL-2) receptor γ chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/87db732a1478ef8759078e0fbed0c6f760cac544

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hematology

In Molecular Biology

Citations in the corpus

SUV39H2 methylates and stabilizes LSD1 by inhibiting polyubiquitination in human cancer cells (2015, background): “Previous data have also indicated that LSD1 functioned as an essential regulator of leukemia stem cell (LSC) potential [39], and its inhibition could reactivate the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [40].”
Histone Modifications and Cancer. (2016, background): “HDAC, histone deacetylase; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; AML, acute myelogenous leukemia; HCC, hepatocellular carcinoma; ER-a, estrogen receptor a; GBM, glioblastoma multiforme; GDH, glutamate dehydrogenase; IHC, immunohistochemistry; NSCLC, non-small-cell lun”
Cancer epigenetics: from mechanism to therapy. (2012, background): “Mutations in IDH1 and IDH2 are seen in up to 70% of patients with secondary glioblastoma mutiforme and are also noted as recurrent mutations in a range of myeloid malignancies, most notably AML (Cimmino et al., 2011).”