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Acute myeloid leukemia

LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML

A Correction to this article was published on 05 March 2019

This article has been updated

Abstract

LSD1 has emerged as a promising epigenetic target in the treatment of acute myeloid leukemia (AML). We used two murine AML models based on retroviral overexpression of Hoxa9/Meis1 (H9M) or MN1 to study LSD1 loss of function in AML. The conditional knockout of Lsd1 resulted in differentiation with both granulocytic and monocytic features and increased ATRA sensitivity and extended the survival of mice with H9M-driven AML. The conditional knockout led to an increased expression of multiple genes regulated by the important myeloid transcription factors GFI1 and PU.1. These include the transcription factors GFI1B and IRF8. We also compared the effect of different irreversible and reversible inhibitors of LSD1 in AML and could show that only tranylcypromine derivatives were capable of inducing a differentiation response. We employed a conditional knock-in model of inactive, mutant LSD1 to study the effect of only interfering with LSD1 enzymatic activity. While this was sufficient to initiate differentiation, it did not result in a survival benefit in mice. Hence, we believe that targeting both enzymatic and scaffolding functions of LSD1 is required to efficiently treat AML. This finding as well as the identified biomarkers may be relevant for the treatment of AML patients with LSD1 inhibitors.

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Change history

  • 05 March 2019

    The original version of this Article contained an error in the Acknowledgements section.

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Acknowledgements

We thank the High Throughput Sequencing unit of the DKFZ Genomics and Proteomics Core Facility and the DKTK Cancer Genomics Core Unit Frankfurt for providing excellent library preparation and RNA sequencing services. We thank Alexandra Walter from the Institute of Pharmaceutical Sciences in Freiburg for technical assistance with the synthesis of used compounds. We also thank the team from the Cytology Lab of the Department of Medicine II, Hematology/Oncology for excellent staining of cytospins and blood smears. This work was performed as part of the LSD1 as Anticancer target in the Clinic and In drug Discovery (LACID) Joint Initiative of the German Cancer Consortium (DKTK). TB was supported by the Deutsche Forschungsgemeinschaft (DFG) (Grants BE 4198/1-1 and BE 4198/2-1) and by the LOEWE programs “Onkogene Signaltransduktion Frankfurt” (OSF) and “Zentrum für Zell- und Gentherapie Frankfurt (CGT)”. CK, JS and LV were supported by a Max-Eder-Fellowship of the Deutsche Krebshilfe and the Fritz-Thyssen-Foundation. ML, RS and MJ were supported by the DFG CRC 992 (MEDEP).

Author contributions

TB conceived the study together with RS, HS, ML, MJ and CK. JB designed and performed the majority of the experiments and subsequent data analysis. NK designed and performed the immunoprecipitation experiment. A-MM assisted in cell culture and mouse transplantation experiments. SM contributed to the mouse transplantation experiments. JS-F and MS synthesized and provided LSD1 inhibitors and advised on their use. DD, KA-E-A and SAW helped with the generation and analyzed the RNA sequencing data. GG performed combination treatment experiments with HL60. MT, EM and RS generated and provided the Lsd1cKO and Lsd1cKI mouse models. GB established and provided primary human AML cultures. JS, LV and CK contributed the Gfi1 KD data and the GficKO mouse model.

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Correspondence to Tobias Berg.

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TB served as a consultant to Riemser Pharma GmbH and received travel funding from Incyte, Abbvie, Astellas, Alexion and Celgene. GB received research funding and honoraria from Novartis, honoraria from Amgen and Celgene and travel funding from Astellas, Janssen, Jazz Pharmaceuticals and Celgene. ML received research funding from Janssen Cilag, study drug support from Ratiopharm and travel funding from Janssen Cilag and Celgene.

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Barth, J., Abou-El-Ardat, K., Dalic, D. et al. LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML. Leukemia 33, 1411–1426 (2019). https://doi.org/10.1038/s41375-018-0375-7

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