puc-header

IDH1 Mutation Enhances Catabolic Flexibility and Mitochondrial Dependencies to Favor Drug Resistance in Acute Myeloid Leukemia

69 Pages Posted: 18 Jan 2019 Sneak Peek Status: Review Complete

See all articles by Lucille Stuani

Lucille Stuani

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Marie Sabatier

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Pierre Millard

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Tony Palama

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Nathalie Poupin

National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB

Estelle Saland

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Claudie Bosc

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Laure Tonini

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Lara Gales

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Camille Montersino

Aix-Marseille University - Institut Paoli-Calmettes

Florence Castelli

MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments

Tony Kaoma

Proteome and Genome Reserch Unit

Thomas Farge

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Nicolas Broin

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Madi Cissé

University of Montpellier - Institute for Cancer Research in Montpellier

Mohsen Hosseini

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Clément Larrue

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Feng Wang

University of Texas at Houston - Department of Genomic Medicine

Natalia Baran

University of Texas at Houston - Department of Genomic Medicine

Nathalie Saint-Laurent

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Pierre-Luc Mouchel

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Marine Fraisse

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Mathilde Gotanègre

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Noémie Gadaud

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Nesrine Aroua

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Cédric Cassan

University of Bordeaux - Fruit Biology and Pathology

Laurent Fernando

University of Toulouse 1 - Toxalim INRA laboratory

Evgenia Turtoi

University of Montpellier - Institute for Cancer Research in Montpellier

Héléna Boutzen

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Laurie Gayte

University of Montpellier - Institute for Cancer Research in Montpellier

Kiyomi Morita

University of Texas at Houston - Department of Genomic Medicine

Andrew M. Futreal

University of Texas at Houston - Department of Genomic Medicine

Maud Heuillet

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Lindsay Peyriga

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Emeline Chu-Van

MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments

Laurent Le Cam

University of Montpellier - Institute for Cancer Research in Montpellier

Martin Carroll

University of Pennsylvania - Division of Hematology & Oncology

Mary A. Selak

University of Pennsylvania - Division of Hematology & Oncology

Norbert Vey

Aix-Marseille University

Claire Calmettes

Centre Hospitalier Universitaire (CHU) de Bordeaux - Clinical Hematology Service

Arnaud Pigneux

Centre Hospitalier Universitaire (CHU) de Bordeaux - Clinical Hematology Service

Audrey Bidet

Centre Hospitalier Universitaire (CHU) de Bordeaux - Biological Hematology Service

Rémy Castellano

Aix-Marseille University - Institut Paoli-Calmettes

Christophe Junot

MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments

Andrei Turtoi

University of Montpellier - Institute for Cancer Research in Montpellier

Guillaume Cazals

University of Montpellier - Laboratory of Physical Measurements

Justine Bertrand-Michel

National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB

Pierre Bories

Onco-Occitanie Regional Oncology Network

Joe Marszalek

University of Texas at Houston - Department of Genomic Medicine

Courtney Dinardo

University of Texas at Houston - MD Anderson Cancer Center

Koichi Takahashi

University of Texas at Houston - MD Anderson Cancer Center

Marina Konopleva

University of Texas at Houston - MD Anderson Cancer Center

Laetitia K. Linares

University of Montpellier - Institute for Cancer Research in Montpellier

Yves Gibon

University of Bordeaux - Fruit Biology and Pathology

Yves Collette

Aix-Marseille University - Institut Paoli-Calmettes

Frédéric Lopez

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Floriant Bellvert

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Fabien Jourdan

National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB

Christian Récher

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

Jean-Charles Portais

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Jean-Emmanuel Sarry

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

More...

Abstract

Isocitrate dehydrogenases (IDH) are involved in redox control and central metabolism. We hypothesized that key metabolic fluxes are selectively reprogrammed to maintain biosynthetic homeostasis and lower drug responses in IDH mutant acute myeloid leukemia cells. Here we show that metabolic reprogramming initiated by IDH1 mutation leads to marked increases in glucose, glutamine and fatty acid catabolism that along with enhancement of wild-type IDH enzyme activity contribute to provision of α-KG required for 2-HG synthesis and to replenish Krebs cycle intermediates for biosynthetic reactions, oxygen consumption and ATP production. Mechanistically, this occurs through both methylation-driven CEBPα activation of FAO and reprogramming of systemic metabolic fluxes through other pathways that augment catabolic flexibility. Consequently, this catabolic flexibility enhances Krebs cycle and OxPHOS activities that are not necessarily rescued by IDH mutant inhibitors or 2-HG reduction. This renders IDH1 mutant cells more resistant to chemotherapeutics but more susceptible to mitochondrial inhibition. Our findings provide a scientific rationale for innovative combinatory targeted therapies to treat this subgroup of patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.

Suggested Citation

Stuani, Lucille and Sabatier, Marie and Millard, Pierre and Palama, Tony and Poupin, Nathalie and Saland, Estelle and Bosc, Claudie and Tonini, Laure and Gales, Lara and Montersino, Camille and Castelli, Florence and Kaoma, Tony and Farge, Thomas and Broin, Nicolas and Cissé, Madi and Hosseini, Mohsen and Larrue, Clément and Wang, Feng and Baran, Natalia and Saint-Laurent, Nathalie and Mouchel, Pierre-Luc and Fraisse, Marine and Gotanègre, Mathilde and Gadaud, Noémie and Aroua, Nesrine and Cassan, Cédric and Fernando, Laurent and Turtoi, Evgenia and Boutzen, Héléna and Gayte, Laurie and Morita, Kiyomi and Futreal, Andrew M. and Heuillet, Maud and Peyriga, Lindsay and Chu-Van, Emeline and Le Cam, Laurent and Carroll, Martin and Selak, Mary A. and Vey, Norbert and Calmettes, Claire and Pigneux, Arnaud and Bidet, Audrey and Castellano, Rémy and Junot, Christophe and Turtoi, Andrei and Cazals, Guillaume and Bertrand-Michel, Justine and Bories, Pierre and Marszalek, Joe and Dinardo, Courtney and Takahashi, Koichi and Konopleva, Marina and Linares, Laetitia K. and Gibon, Yves and Collette, Yves and Lopez, Frédéric and Bellvert, Floriant and Jourdan, Fabien and Récher, Christian and Portais, Jean-Charles and Sarry, Jean-Emmanuel, IDH1 Mutation Enhances Catabolic Flexibility and Mitochondrial Dependencies to Favor Drug Resistance in Acute Myeloid Leukemia (September 26, 2018). Available at SSRN: https://ssrn.com/abstract=3255557 or http://dx.doi.org/10.2139/ssrn.3255557
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Lucille Stuani

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Marie Sabatier

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Pierre Millard

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Place Anatole France
Toulouse Cedex, F-31042
France

Tony Palama

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Place Anatole France
Toulouse Cedex, F-31042
France

Nathalie Poupin

National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB

Toulouse, F-31077
France

Estelle Saland

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Claudie Bosc

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Laure Tonini

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Lara Gales

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Place Anatole France
Toulouse Cedex, F-31042
France

Camille Montersino

Aix-Marseille University - Institut Paoli-Calmettes

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Florence Castelli

MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments

Toulouse, F-31077
France

Tony Kaoma

Proteome and Genome Reserch Unit

84, rue Val Fleuri
Luxembourg
Luxembourg

Thomas Farge

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Nicolas Broin

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Madi Cissé

University of Montpellier - Institute for Cancer Research in Montpellier

163 rue Auguste Broussonnet
France

Mohsen Hosseini

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Clément Larrue

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Feng Wang

University of Texas at Houston - Department of Genomic Medicine

1515 Holocombe Blvd
Houston, TX 77030
United States

Natalia Baran

University of Texas at Houston - Department of Genomic Medicine

1515 Holocombe Blvd
Houston, TX 77030
United States

Nathalie Saint-Laurent

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Pierre-Luc Mouchel

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Marine Fraisse

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Mathilde Gotanègre

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Noémie Gadaud

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Nesrine Aroua

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Cédric Cassan

University of Bordeaux - Fruit Biology and Pathology

Bordeaux
France

Laurent Fernando

University of Toulouse 1 - Toxalim INRA laboratory

41 Allées Jules Guesde - CS 61321
Toulouse
France

Evgenia Turtoi

University of Montpellier - Institute for Cancer Research in Montpellier

163 rue Auguste Broussonnet
France

Héléna Boutzen

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Laurie Gayte

University of Montpellier - Institute for Cancer Research in Montpellier

163 rue Auguste Broussonnet
France

Kiyomi Morita

University of Texas at Houston - Department of Genomic Medicine

1515 Holocombe Blvd
Houston, TX 77030
United States

Andrew M. Futreal

University of Texas at Houston - Department of Genomic Medicine

1515 Holocombe Blvd
Houston, TX 77030
United States

Maud Heuillet

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Place Anatole France
Toulouse Cedex, F-31042
France

Lindsay Peyriga

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Place Anatole France
Toulouse Cedex, F-31042
France

Emeline Chu-Van

MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments

Toulouse, F-31077
France

Laurent Le Cam

University of Montpellier - Institute for Cancer Research in Montpellier

163 rue Auguste Broussonnet
France

Martin Carroll

University of Pennsylvania - Division of Hematology & Oncology

Philadelphia, PA 19104
United States

Mary A. Selak

University of Pennsylvania - Division of Hematology & Oncology

Philadelphia, PA 19104
United States

Norbert Vey

Aix-Marseille University

3 Avenue Robert Schuman
3 Avenue Robert Schuman,
Aix-en-Provence, 13628
France

Claire Calmettes

Centre Hospitalier Universitaire (CHU) de Bordeaux - Clinical Hematology Service

Place Amélie Raba Léon
Bordeaux
France

Arnaud Pigneux

Centre Hospitalier Universitaire (CHU) de Bordeaux - Clinical Hematology Service

Place Amélie Raba Léon
Bordeaux
France

Audrey Bidet

Centre Hospitalier Universitaire (CHU) de Bordeaux - Biological Hematology Service

Place Amélie Raba Léon
Bordeaux
France

Rémy Castellano

Aix-Marseille University - Institut Paoli-Calmettes

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Christophe Junot

MetaboHUB-Paris - Laboratoire d’Etude du Métabolisme des Médicaments

Toulouse, F-31077
France

Andrei Turtoi

University of Montpellier - Institute for Cancer Research in Montpellier

163 rue Auguste Broussonnet
France

Guillaume Cazals

University of Montpellier - Laboratory of Physical Measurements

163 rue Auguste Broussonnet
Bordeaux
France

Justine Bertrand-Michel

National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB

Toulouse, F-31077
France

Pierre Bories

Onco-Occitanie Regional Oncology Network

Toulouse
France

Joe Marszalek

University of Texas at Houston - Department of Genomic Medicine

1515 Holocombe Blvd
Houston, TX 77030
United States

Courtney Dinardo

University of Texas at Houston - MD Anderson Cancer Center

1515 Holocombe Blvd
Houston, TX 77030
United States

Koichi Takahashi

University of Texas at Houston - MD Anderson Cancer Center

1515 Holocombe Blvd
Houston, TX 77030
United States

Marina Konopleva

University of Texas at Houston - MD Anderson Cancer Center

1515 Holocombe Blvd
Houston, TX 77030
United States

Laetitia K. Linares

University of Montpellier - Institute for Cancer Research in Montpellier

163 rue Auguste Broussonnet
France

Yves Gibon

University of Bordeaux - Fruit Biology and Pathology

Bordeaux
France

Yves Collette

Aix-Marseille University - Institut Paoli-Calmettes

3 Avenue Robert Schuman
Aix-en-Provence, 13628
France

Frédéric Lopez

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Floriant Bellvert

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Place Anatole France
Toulouse Cedex, F-31042
France

Fabien Jourdan

National Infrastructure of Metabolomics and Fluxomics - MetaToul-MetaboHUB

Toulouse, F-31077
France

Christian Récher

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Jean-Charles Portais

University of Toulouse 1 - Laboratory of Engineering of Biological Systems and Processes (LISBP)

Place Anatole France
Toulouse Cedex, F-31042
France

Jean-Emmanuel Sarry (Contact Author)

University of Toulouse 3, Paul Sabatier University - Toulouse Cancer Research Center ( email )

118 Route de Narbonne
Toulouse cedex 9, F-31062
France

Click here to go to Cell.com

Go to Cell.com

Paper statistics

Abstract Views
351
Downloads
20