Eradication of Central Nervous System Leukemia of T-Cell Origin with a Brain-Permeable LSD1 Inhibitor.

Abstract

PURPOSE:

Lysine-specific demethylase 1 (LSD1) regulates several biological processes via the bifunctional modulation of enhancer functions. Recently, we reported that LSD1 overexpression is a founder abnormality of T-cell leukemogenesis and is maintained in fully transformed T-cell acute lymphoblastic leukemia (T-ALL) cells. On the basis of this finding, we attempted to develop novel LSD1 inhibitors effective for T-ALL with central nervous system (CNS) involvement.

EXPERIMENTAL DESIGN:

We chemically modified the prototype LSD inhibitor tranylcypromine (TCP) and screened for cytotoxicity against TCP-resistant T-ALL cell lines. In vivo efficacy of novel LSD1 inhibitors was examined in immunodeficient mice transplanted with luciferase-expressing T-ALL cell lines, which faithfully reproduce human T-ALL with CNS involvement.

RESULTS:

We found robust cytotoxicity against T-ALL cells, but not normal bone marrow progenitors, for two N-alkylated TCP derivatives, S2116 and S2157. The two compounds induced apoptosis in TCP-resistant T-ALL cells in vitro and in vivo by repressing transcription of the NOTCH3 and TAL1 genes through increased H3K9 methylation and reciprocal H3K27 deacetylation at superenhancer regions. Both S2116 and S2157 significantly retarded the growth of T-ALL cells in xenotransplanted mice and prolonged the survival of recipients as monotherapy and in combination with dexamethasone. Notably, S2157 could almost completely eradicate CNS leukemia because of its ability to efficiently pass through the blood-brain barrier.

CONCLUSIONS:

These findings provide a molecular basis and rationale for the inclusion of a brain-permeable LSD1 inhibitor, S2157, in treatment strategies for T-ALL with CNS involvement.

• Authors: Shiori Saito, Jiro Kikuchi, Daisuke Koyama, Shin Sato, Hiroo Koyama, Naoki Osada, Yoshiaki Kuroda, Koshi Akahane, Takeshi Inukai, Takashi Umehara, Yusuke Furukawa
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 5 Pg. 1601-1611 (03 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30518632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Receptor, Notch3
• T-Cell Acute Lymphocytic Leukemia Protein 1
• TAL1 protein, human
• Histone Demethylases
• KDM1A protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Biomarkers, Tumor
• Blood-Brain Barrier (drug effects, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Central Nervous System Neoplasms (diagnosis, drug therapy, metabolism, mortality)
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Demethylases (antagonists & inhibitors)
• Humans
• Mice
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (diagnosis, drug therapy, metabolism, mortality)
• Receptor, Notch3 (metabolism)
• T-Cell Acute Lymphocytic Leukemia Protein 1 (metabolism)
• Xenograft Model Antitumor Assays