Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations

We assessed the anti-leukemic activity of 2-deoxy-D-glucose (2-DG) through the modulation of expression of receptor tyrosine kinases commonly mutated in acute myeloid leukemia. We used human leukemic cell lines cells, both in vitro and in vivo, as well as leukemic samples from AML patients to demonstrate the role of 2-DG in tumor cell growth inhibition. 2-DG, through N-linked glycosylation inhibition, affected the cell surface expression and cellular signaling of both FTL3-ITD and mutated c-KIT and induced apoptotic cell death. Leukemic cells harboring these mutated RTKs (MV4-11, MOLM-14, Kasumi-1, TF-1 c-KIT D816V) were the most sensitive to 2-DG treatment in vitro as compared to non-mutated cells. 2-DG activity was also demonstrated in leukemic cells harboring FLT3-TKD mutations resistant to the tyrosine kinase inhibitor quizartinib. Moreover, the anti-leukemic activity of 2-DG was particularly marked in c-KIT mutated cell lines and cell samples from core binding factor-AML patients. In these cells, 2-DG inhibited the cell surface expression of c-KIT, abrogated STAT3 and MAPK/ERK pathways and strongly down-regulated the expression of the receptor resulting in a strong in vivo effect in NOD/SCID mice xenografted with Kasumi-1 cells. Lastly, we showed that 2-DG decreases Mcl-1 protein expression in AML cells and induces sensitization to both the BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w, ABT-737, and cytarabine. In conclusion, 2-DG displays a significant anti-leukemic activity in AML with FLT3-ITD or KIT mutations opening a new therapeutic window in a subset of AML with mutated RTKs.