Page 145 - Haematologica April 2020

Acute Myeloid Leukemia
Mesenchymal stromal cells confer chemoresistance to myeloid leukemia blasts through Side Population functionality
and ABC transporter activation
Laetitia Boutin,1,2 Pierre Arnautou,3 Aurélie Trignol,1 Amandine Ségot,3 Thomas Farge,4 Christophe Desterke,5 Sabrina Soave,2 Denis Clay,5 Emmanuel Raffoux,6 Jean-Emmanuel Sarry,4 Jean-Valère Malfuson,2,3 Jean-Jacques Lataillade,1,2 Marie-Caroline Le Bousse-Kerdilès2*
and Adrienne Anginot2*
*AA and MCLBK contributed equally to this work
1CTSA, IRBA, Clamart; 2Inserm UMR-S-MD1197, Paul Brousse Hospital, Paris 11 University, Villejuif; 3Hematology Department, HIA Percy, Clamart; 4Inserm U1037, Cancer Research Center of Toulouse, University of Toulouse, Toulouse; 5Inserm UMS33, Paul Brousse Hospital, Paris 11 University, Villejuif and 6Adult Hematology Department, Saint Louis Hospital, Paris, France
ABSTRACT
Targeting chemoresistant malignant cells is one of the current major challenges in oncology. Therefore, it is mandatory to refine the char- acteristics of these cells to monitor their survival and develop adapt- ed therapies. This is of particular interest in acute myeloid leukemia (AML), for which the 5-year survival rate only reaches 30%, regardless of the prog- nosis. The role of the microenvironment is increasingly reported to be a key regulator for blast survival. In this context, we demonstrate that contact with mesenchymal stromal cells promotes a better survival of blasts in cul- ture in the presence of anthracycline through the activation of ABC trans- porters. Stroma-dependent ABC transporter activation leads to the induc- tion of a Side Population (SP) phenotype in a subpopulation of primary leukemia blasts through alpha (α)4 engagement. The stroma-promoting effect is reversible and is observed with stromal cells isolated from either healthy donors or leukemia patients. Blasts expressing an SP phenotype are mostly quiescent and are chemoresistant in vitro and in vivo in patient- derived xenograft mouse models. At the transcriptomic level, blasts from the SP are specifically enriched in the drug metabolism program. This detoxification signature engaged in contact with mesenchymal stromal cells represents promising ways to target stroma-induced chemoresistance of AML cells.
Introduction
Acute myeloid leukemias (AML) represent a set of hemopathies characterized by a clonal expansion in bone marrow (BM) and blood of immature myeloid cells, called blasts, blocked at different stages of differentiation. AML can be classified according to the degree of immaturity [as according to the French-American- British (FAB) classification] or depending on the cytogenetic or molecular events observed in patients (according to the World Health Organization 2016 criteria).1 AML are also subdivided into three groups that condition therapy: favorable AML, which may be cured without hematopoietic stem cell transplant, and inter- mediate and adverse AML which may require an allogenic graft. Despite the sig- nificant progress made in supportive care, there has been no radical change in the prognosis of AML; the 5-year survival rate is 30% for all groups of AML and 10% for adverse AML. The conventional chemotherapy based on the injection of a nucleoside analog combined with an anthracycline is used to kill AML cells. However, many patients relapse, mainly due to the persistence of rare chemore-
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):987-998
Correspondence:
ADRIENNE ANGINOT
adrienne.anginot@inserm.fr
Received: December 14, 2018. Accepted: July 5, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2018.214379
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/987
©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(4)
987
ARTICLE