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

 Weihsu Claire Chen, Stefanie Göllner, Louise Howell. Nat. Med. (2012) 18, 605-611

Speaker: Jia-Ying Hung (洪家瑩)                             Time: 14:10~15:00, Sep. 18, 2013

Commentator: Dr. Yao Chang (張堯 博士)             Place: Room 601

Abstract

   Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). APL produces PML-RARA fusion protein due to gene translocation of chromosome 15 and 17 that carry promyelocytic leukemia (PML) and retinoic acid receptor alfa (RARA) gene. All-trans retinoic acid (ATRA), which is classified as a retinoid, is a non-chemo drug that has been utilizing for treatment of APL. ATRA treatment triggers differentiation of less mature cells which leads to clinical remission. However, ATRA-based therapy gets poor response in non-APL AML patients. ATRA resistence in AML has been atributed to a failure in proper transcription activation of retinoic acid receptor (RAR) target genes by ATRA (1). When compared to normal meyloid cells, AML cells have reduced histone 3 lysine 4 dimethylation (H3K4^me2) on RARA promoter resulting in loss of RARα2 expression and abnormal expression of differentiation associated genes that are RAR down stream (2). Lysine-specific demethylase LSD1 (KDMA1) mediating demethylation of methylated lysines is highly expressed in AML cells (3). It is suspected that small-molecule inhibitors targeting LSD1 (LSD1i) may promote ATRA-induced differentiation. In this study, the authors used two structurally unrelated LSD1 inhibitors, tranylcypromine (TCP) and 1,15-bis{N5-[3,3-(diphenyl)propyl]-N1-biguanido}-4,12-diazapentadecane (2d) to confirm this idea. The results showed that TCP and 2d increased the efficacy of ATRA-induced differentiation both in vitro or in vivo. H3K4me2 occurred at some unique gene loci after combined treatment with TCP and ATRA. Further more, genes associated with myeloid differentiation are upregulated by ATRA plus TCP that is correlated positively with increased in H3K4me2 at -2000 or + 2000 bp from transcription start sites. In summary, combined treatment with ATRA and TCP may be a promising therapy for AML.

References

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2.      Glasow, A. et al. DNA methylation-independent loss of RARA gene expression in acute myeloid leukemia. Blood 111, 2374–2377 (2008).

3.      Berglund, L. et al. A genecentric Human Protein Atlas for expression profiles based on antibodies. Mol. Cell. Proteomics 7, 2019–2027 (2008).