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15357163mct150163-sup-145489_1_supp_3030910_nq6hq5.ppt (624.5 kB)

Supplementary Figures 1 through 4 and Supplementary Materials and Methods from Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations

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posted on 2023-04-03, 15:25 authored by Clément Larrue, Estelle Saland, François Vergez, Nizar Serhan, Eric Delabesse, Véronique Mansat-De Mas, Marie-Anne Hospital, Jérôme Tamburini, Stéphane Manenti, Jean Emmanuel Sarry, Christian Récher

This file contains additional figures that enrich results presented in the main manuscript. We evaluated the impact of the 2-DG on the expression of both wild-type FLT3 and KIT. Then, we excluded a potential role for cellular protein degradation pathways such as apoptosis or ubiquitin-proteasome pathway in response to 2-DG. We also investigated the subcellular location of FLT3 after 2-DG treatment. In addition, we assessed the impact of the 2-DG on the phosphorylation of Lyn and Akt, Finally, this file contains data on the effects of 2-DG in a rare primary sample patient carrying the FLT3-TKD mutation. Supplementary material and methods for qRT-PCR.

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ARTICLE 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. Mol Cancer Ther; 14(10); 2364–73. ©2015 AACR.