Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes.
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.
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Polina
P
Matre
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Juliana
J
Velez
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rodrigo
R
Jacamo
Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yuan
Y
Qi
Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Xiaoping
X
Su
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Tianyu
T
Cai
Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Steven M
SM
Chan
Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.
Alessia
A
Lodi
Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.
Shannon R
SR
Sweeney
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Helen
H
Ma
Lymphoma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Richard Eric
RE
Davis
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Natalia
N
Baran
CEO of MLL Munich Leukemia Laboratory, Munich, Germany.
Torsten
T
Haferlach
Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Xiaohua
X
Su
Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Elsa Renee
ER
Flores
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Doriann
D
Gonzalez
Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sergej
S
Konoplev
The Centre for Drug Research and Development Biologics, Vancouver, British Columbia, Canada.
Ismael
I
Samudio
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Courtney
C
DiNardo
Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Ravi
R
Majeti
Medical Biophysics, Princess Margaret Hospital / Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Aaron D
AD
Schimmer
Analytical Chemistry, Pharmacology, Spectroscopy, Calithera Biosciences, South San Francisco, CA, USA.
Weiqun
W
Li
Analytical Chemistry, Pharmacology, Spectroscopy, Calithera Biosciences, South San Francisco, CA, USA.
Taotao
T
Wang
Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.
Stefano
S
Tiziani
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Marina
M
Konopleva
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020033:Protein Isoforms; D013440:Sulfides / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D044482:Benzeneacetamides; C000593334:CB-839; D004791:Enzyme Inhibitors; D005977:Glutarates; D020033:Protein Isoforms; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005973:Glutamine; C019417:alpha-hydroxyglutarate; D018698:Glutamic Acid; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human; C579480:GLS protein, human; D005972:Glutaminase
differentiation therapy; glutamine; leukemia; metabolism; microenvironment