Abstract
We assessed the antileukemic activity of 2-deoxy-d-glucose (2-DG) through the modulation of expression of receptor tyrosine kinases (RTK) commonly mutated in acute myeloid leukemia (AML). 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, and TF-1 c-KIT D816V) were the most sensitive to 2-DG treatment in vitro as compared with nonmutated cells. 2-DG activity was also demonstrated in leukemic cells harboring FLT3-TKD mutations resistant to the tyrosine kinase inhibitor (TKI) quizartinib. Moreover, the antileukemic 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 downregulated the expression of the receptor resulting in a strong in vivo effect in NOD/SCID mice xenografted with Kasumi-1 cells. Finally, 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 antileukemic activity in AML with FLT3-ITD or KIT mutations, opening a new therapeutic window in a subset of AML with mutated RTKs.
Highlights
Acute myeloid leukemia (AML) is characterized by the clonal expansion and accumulation of immature blasts in the bone marrow [1]
Because the proapoptotic effects of 2-DG in leukemic cell lines appeared to correlate with the expression of membrane receptor tyrosine kinases (RTK), such as FLT3-internal tandem duplications (ITD) and c-KIT, we assessed the activity of 2DG in primary cells from patients according to these mutations (Supplementary Table S2). 2-DG induced apoptosis in primary AML samples with FLT3-ITD (n 1⁄4 9) or c-KIT-D816V (n 1⁄4 5) in a dose-dependent manner, whereas FLT3-wt samples were less sensitive the difference was not statistically significant (Fig. 1G)
It has been demonstrated that fluvastatin and others compounds of the statin family were able to impair FLT3 glycosylation, leading to a reduction in cell-surface expression and an increase in cell death, in leukemic cell lines with RTK mutations [42]
Summary
Acute myeloid leukemia (AML) is characterized by the clonal expansion and accumulation of immature blasts in the bone marrow [1]. FLT3 (Fms-like tyrosine kinase 3) and c-KIT are two transmembrane glycoprotein members of the class III RTKs expressed in early hematopoietic progenitors involved in cell proliferation, differentiation, and survival [3,4,5] Their role in leukemogenesis has been extensively studied, setting them as attractive therapeutic targets in some subsets of AML [6, 7]. Similar to other membrane receptors for growth factors, FLT3 and c-KIT undergo a complex maturation process, in which they undergo N-linked glycosylation in the ER before being transported to the Golgi apparatus where they are modified by further complex glycosylations and subsequently transported to the cell surface [33] This maturation process is affected by constitutive tyrosine phosphorylations induced by mutations of these receptors. We assessed the potential anti-AML activity of 2DG through the modulation of RTKs expression and signalization as well as Mcl-1 expression, focusing on AML models in which mutated RTKs are intimately linked to leukemogenesis
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