Abstract：
:Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.
journal_name
Bloodjournal_title
Bloodauthors
Jacque N,Ronchetti AM,Larrue C,Meunier G,Birsen R,Willems L,Saland E,Decroocq J,Maciel TT,Lambert M,Poulain L,Hospital MA,Sujobert P,Joseph L,Chapuis N,Lacombe C,Moura IC,Demo S,Sarry JE,Recher C,Mayeux P,Tamburdoi
10.1182/blood-2015-01-621870subject
Has Abstractpub_date
2015-09-10 00:00:00pages
1346-56issue
11eissn
0006-4971issn
1528-0020pii
blood-2015-01-621870journal_volume
126pub_type
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