Page 129 - 2020_08-Haematologica-web

Acute Myeloid Leukemia
Tuning mTORC1 activity dictates the response of acute myeloid leukemia to LSD1 inhibition
Ferrata Storti Foundation
Haematologica 2020 Volume 105(8):2105-2117
Amal Kamal Abdel-Aziz,1,2 Isabella Pallavicini,1 Elena Ceccacci,1 Giuseppe Meroni,3 Mona Kamal Saadeldin,1,4 Mario Varasi3
and Saverio Minucci1,5
1Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 3Experimental Therapeutics IFOM-FIRC Institute of Molecular Oncology Foundation, Milan, Italy; 4Faculty of Biotechnology, October University for Modern Sciences and Arts, 6th October City, Cairo, Egypt and 5Department of Biosciences, University of Milan, Milan, Italy
ABSTRACT
Lysine specific demethylase-1 (LSD1) has been shown to be critical in acute myeloid leukemia (AML) pathogenesis and this has led to the development of LSD1 inhibitors (LSD1i) which are currently tested in clinical trials. Nonetheless, preclinical studies reported that AML cells fre- quently exhibit intrinsic resistance to LSD1 inhibition, and the molecular basis for this phenomenon is largely unknown. We explored the potential involvement of mammalian target of rapamycin (mTOR) in mediating the resistance of leukemic cells to LSD1i. Strikingly, unlike sensitive leukemias, mTOR complex 1 (mTORC1) signaling was robustly triggered in resistant leukemias following LSD1 inhibition. Transcriptomic, chromatin immuno- precipitation and functional studies revealed that insulin receptor substrate 1(IRS1)/extracellular-signal regulated kinases (ERK1/2) signaling critically controls LSD1i induced mTORC1 activation. Notably, inhibiting mTOR unlocked the resistance of AML cell lines and primary patient-derived blasts to LSD1i both in vitro and in vivo. In conclusion, mTOR activation might act as a novel pro-survival mechanism of intrinsic as well as acquired resistance to LSD1i, and combination regimens co-targeting LSD1/mTOR could repre- sent a rational approach in AML therapy.
Introduction
Among the novel epigenetic druggable targets in acute myeloid leukemia (AML) therapy, lysine specific histone demethylase 1 (LSD1) has gained attention based on its preferential overexpression in primary AML compared to normal hematopoi- etic stem and progenitor cells.1,2 In cooperation with the oncogenic MLL-AF9 fusion protein, LSD1 actively sustains AML maintenance.3 Moreover, LSD1 inhibition reactivates an all-trans-retinoic acid (ATRA)-dependent differentiation pathway in AML.4 LSD1 overexpression has also been associated with poor prognosis in vari- ous types of tumors including colon and lung cancers.5,6 Mechanistically, LSD1 is a flavin adenine dinucleotide (FAD)-dependent amine oxidase that specifically removes mono- or dimethylated histone H3K4 and H3K9 resulting in context-spe- cific transcriptional repression and activation respectively.7 Apart from chromatin, LSD1 demethylates and hence regulates a wide array of non-histone targets.8,9 All these activities account for the role of LSD1 in regulating tumor proliferation, metastasis and metabolism.2,10,11 We and others have developed LSD1 inhibitors (LSD1i) with potent and selective biochemical profiles and some of which are cur- rently evaluated in clinical trials.12–15 Nonetheless, the preclinical antileukemic activ- ity of LSD1i as a monotherapy is relatively modest.16,17 In solid tumors, specific DNA methylation signatures correlated with the sensitivity to LSD1i.16 However, the molecular mechanisms underlying the differential responsiveness of AML to LSD1i remain largely unknown.
Correspondence:
SAVERIO MINUCCI
saverio.minucci@ieo.it
Received: April 19, 2019.
Accepted: September 16, 2019. Pre-published: September 19, 2019.
doi:10.3324/haematol.2019.224501
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2105
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2020; 105(8)
2105
ARTICLE