Abstract 5482: Antileukemic activity of 2-deoxy-d-glucose in acute myeloid leukemia
Authors: Larrue Clément , Manenti Stéphane , Récher Christian 
Published: May 2015

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by the clonal expansion and accumulation of immature blasts in the bone marrow. Several receptor tyrosine kinases (RTKs), including internal tandem duplication mutations of the Fms-like tyrosine kinase 3 (FLT3-ITD) or mutations of the Proto-oncogene c-Kit (c-Kit N822K or D816V), are involved in the pathogenesis of AML. Another major point of resistance of leukemic cells to chemotherapy is their inability to activate cell death pathways, because of overexpression of anti-apoptotic proteins (Mcl-1, Bcl-2...). In this study we worked on the antileukemic activity of 2-deoxy-d-glucose (2-DG), a glycolysis and N-linked-glycosylation inhibitor, which have been described in different cancer models to sensitize to chemotherapy.

First we evaluated the effects of 2-DG on cell proliferation and apoptosis. We showed that 2-DG inhibited more strongly cell proliferation of MV4-11, MOLM-14, Kasumi-1 and TF1 c-Kit D816V cell lines than U-937. In accordance with this result, 2-DG induced apoptosis in all AML cell lines previously cited excluding U-937. We also used the murine model BaF/3 stably transfected with FLT3-ITD, c-Kit D816V or BCR-ABL, and showed that cells transformed with a membrane tyrosine kinase were more sensitize to 2-DG than cell expressing the cytoplasmic oncogene BCR-ABL. Moreover, 2-DG induced apoptosis in primary FLT3-ITD AML samples (n=9) or c-Kit D816V mutated samples (n=5). At molecular level, 2-DG inhibited N-linked-glycosylation of FLT3-ITD and c-Kit mutants both in cell lines and primary AML samples, leading to a decrease of cell surface expression of these RTKs. We also showed that 2-DG overcomes the resistance to AC-220 in a MOLM-14 ITD/TKD model, by triggering the deglycosylation of the receptor. Furthermore, 2-DG exposure decreased ERK and STAT3/5 signaling but, surprisingly, not the AKT pathway in FLT3-ITD or c-Kit mutated models. Cell exposure to 2-DG and D-mannose, which restores N-linked-glycosylation but not glycolysis, demonstrated that 2-DG induced apoptosis and inhibition of RTKs cell surface expression are independent of the effects of 2-DG on glycolysis.

In another part, we have demonstrated that 2-DG was able to decrease protein expression of the anti apoptotic protein mcl-1 in sensitive and resistant cells as well as in primary patient samples. These results correlated with the fact that in some cells, like lymphoma cells, mcl-1 synthesis is glycolysis-dependent. We took advantage of this decrease to associate the 2-DG with cytotoxic agents ABT-737 or cytarabine (Ara-C) and showed that these combinations (Ara-C+2-DG or ABT-737+2-DG) were synergistic.

Our study shows that dual targeting of glycolysis and N-linked-glycosylation is an attractive therapeutic strategy in acute myeloid leukemia.

Note: This abstract was not presented at the meeting.

Citation Format: Clément Larrue, Stéphane Manenti, Christian Récher. Antileukemic activity of 2-deoxy-d-glucose in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5482. doi:10.1158/1538-7445.AM2014-5482