Oncotarget

Research Papers:

Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes

Polina Matre, Juliana Velez, Rodrigo Jacamo, Yuan Qi, Xiaoping Su, Tianyu Cai, Steven M. Chan, Alessia Lodi, Shannon R. Sweeney, Helen Ma, Richard Eric Davis, Natalia Baran, Torsten Haferlach, Xiaohua Su, Elsa Renee Flores, Doriann Gonzalez, Sergej Konoplev, Ismael Samudio, Courtney DiNardo, Ravi Majeti, Aaron D. Schimmer, Weiqun Li, Taotao Wang, Stefano Tiziani and Marina Konopleva _

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Oncotarget. 2016; 7:79722-79735. https://doi.org/10.18632/oncotarget.12944

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Abstract

Polina Matre1,*, Juliana Velez1,*, Rodrigo Jacamo1, Yuan Qi2, Xiaoping Su2, Tianyu Cai1, Steven M. Chan3, Alessia Lodi4, Shannon R. Sweeney4, Helen Ma1, Richard Eric Davis5, Natalia Baran1, Torsten Haferlach6, Xiaohua Su7, Elsa Renee Flores7, Doriann Gonzalez1, Sergej Konoplev8, Ismael Samudio9, Courtney DiNardo1, Ravi Majeti3, Aaron D. Schimmer10, Weiqun Li11, Taotao Wang11, Stefano Tiziani4, Marina Konopleva1

1Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

3Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

4Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA

5Lymphoma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

6CEO of MLL Munich Leukemia Laboratory, Munich, Germany

7Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

8Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

9The Centre for Drug Research and Development Biologics, Vancouver, British Columbia, Canada

10Medical Biophysics, Princess Margaret Hospital / Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

11Analytical Chemistry, Pharmacology, Spectroscopy, Calithera Biosciences, South San Francisco, CA, USA

*These authors have contributed equally to this work

Correspondence to:

Marina Konopleva, email: mkonople@mdanderson.org

Keywords: leukemia, metabolism, glutamine, microenvironment, differentiation therapy

Received: June 08, 2016    Accepted: October 13, 2016    Published: October 27, 2016

ABSTRACT

Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes.


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