Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism
Thomas Farge
(1)
,
Estelle Saland
(2)
,
Fabienne de Toni
(3)
,
Nesrine Aroua
(1)
,
Mohsen Hosseini
(1)
,
Robin Perry
,
Claudie Bosc
(1)
,
Mayumi Sugita
(4)
,
Lucille Stuani
(5)
,
Marine Fraisse
(1)
,
Sarah J. Scotland
(6)
,
Clément Larrue
(5)
,
Héléna Boutzen
(5)
,
Virginie Feliu
(1)
,
Marie-Laure Nicolau-Travers
(7)
,
Stéphanie Cassant-Sourdy
(2)
,
Nicolas Broin
(1)
,
Marion David
(8)
,
Nizar Serhan
(2)
,
Audrey Sarry
(1)
,
Suzanne Tavitian
(1)
,
Tony Kaoma
(9)
,
Laurent Vallar
(9)
,
Jason S. Iacovoni
(10)
,
Laetitia K. Linares
(11)
,
Camille Montersino
(12)
,
Remy Castellano
(12)
,
Emmanuel Griessinger
(13)
,
Yves Collette
(12)
,
Olivier Duchamp
(14)
,
Yara Barreira
(15)
,
Pierre Hirsch
(16)
,
Tony L Palama
(17)
,
Lara Gales
(17)
,
François Delhommeau
(18)
,
Barbara Garmy-Susini
(2)
,
Jean-Charles Portais
(17)
,
François Vergez
(5)
,
Mary Selak
(4)
,
Gwenn Danet-Desnoyers
(4)
,
Martin Carroll
(4)
,
Christian Recher
(19)
,
Jean-Emmanuel Sarry
(1)
1
IUCT Oncopole - UMR 1037 -
Institut Universitaire du Cancer de Toulouse - Oncopole
2 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
3 LMPM - Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31]
4 University of Pennsylvania
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 Equipe 11-E.Moyal/C.Toulas
7 LCC - Laboratoire de chimie de coordination
8 Laboratoire de biologie clinique [Rouen]
9 LIH - Luxembourg Institute of Health
10 I2MR - Institut de médecine moléculaire de Rangueil
11 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
12 CRCM - Centre de Recherche en Cancérologie de Marseille
13 C3M - Centre méditerranéen de médecine moléculaire
14 Oncodesign [Dijon]
15 UMS006 Service d'Experimentation Animale
16 Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine]
17 LISBP - Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés
18 Service d'immunologie et hématologies biologiques [CHU Saint-Antoine]
19 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
2 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
3 LMPM - Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31]
4 University of Pennsylvania
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 Equipe 11-E.Moyal/C.Toulas
7 LCC - Laboratoire de chimie de coordination
8 Laboratoire de biologie clinique [Rouen]
9 LIH - Luxembourg Institute of Health
10 I2MR - Institut de médecine moléculaire de Rangueil
11 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
12 CRCM - Centre de Recherche en Cancérologie de Marseille
13 C3M - Centre méditerranéen de médecine moléculaire
14 Oncodesign [Dijon]
15 UMS006 Service d'Experimentation Animale
16 Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine]
17 LISBP - Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés
18 Service d'immunologie et hématologies biologiques [CHU Saint-Antoine]
19 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
Thomas Farge
- Function : Author
- PersonId : 784319
- ORCID : 0000-0002-4390-8073
Estelle Saland
- Function : Author
- PersonId : 764704
- ORCID : 0000-0001-8521-3061
Mohsen Hosseini
- Function : Author
- PersonId : 784320
- ORCID : 0000-0002-1686-8512
Robin Perry
- Function : Author
Claudie Bosc
- Function : Author
- PersonId : 784321
- ORCID : 0000-0003-1435-3475
Clément Larrue
- Function : Author
- PersonId : 784030
- ORCID : 0000-0001-5827-8433
- IdRef : 194902137
Nicolas Broin
- Function : Author
- PersonId : 784322
- ORCID : 0000-0003-3648-8426
Marion David
- Function : Author
- PersonId : 768797
- ORCID : 0000-0002-7705-0079
Tony Kaoma
- Function : Author
- PersonId : 784323
- ORCID : 0000-0002-1269-4826
Laetitia K. Linares
- Function : Author
- PersonId : 1036785
Camille Montersino
- Function : Author
- PersonId : 784324
- ORCID : 0000-0001-7024-5327
Yves Collette
- Function : Author
- PersonId : 752645
- IdHAL : yves-collette
- ORCID : 0000-0001-5359-7099
- IdRef : 070509891
Pierre Hirsch
- Function : Author
- PersonId : 765239
- ORCID : 0000-0002-5300-2566
Tony L Palama
- Function : Author
- PersonId : 173912
- IdHAL : tony-palama
- ORCID : 0000-0002-4519-4502
- IdRef : 112998070
Lara Gales
- Function : Author
- PersonId : 976067
- ORCID : 0000-0002-1233-2032
Jean-Charles Portais
- Function : Author
- PersonId : 1097795
- ORCID : 0000-0002-3480-0933
- IdRef : 058637397
Martin Carroll
- Function : Author
- PersonId : 784325
- ORCID : 0000-0002-5622-3735
Christian Recher
- Function : Author
- PersonId : 975639
- ORCID : 0000-0002-3332-4525
- IdRef : 134542487
Jean-Emmanuel Sarry
- Function : Author
- PersonId : 1019748
Abstract
Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease.Significance: AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36-FAO-OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. Cancer Discov; 7(7); 716-35. ©2017 AACR.See related commentary by Schimmer, p. 670This article is highlighted in the In This Issue feature, p. 653.