AG-221 induces the differentiation of IDH2R140Q blasts along myeloid lineages in primary human AML xenograft models. AG-221 induces the differentiation.

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AG-221 induces the differentiation of IDH2R140Q blasts along myeloid lineages in primary human AML xenograft models. AG-221 induces the differentiation of IDH2R140Q blasts along myeloid lineages in primary human AML xenograft models. A, Percentage of hCD45+ cells in the blood expressing any of the cell surface markers associated with differentiation along the monocytic/macrophage and granulocytic lineages (CD11b, CD14, CD15, or CD24) following treatment with AG-221 30 mg/kg b.i.d. or vehicle for 38 days, starting on day 0 (mean ± SD of combined data obtained from AML-1 and AML-2 is shown, n = 3 for both vehicle and AG-221). Statistical significance of AG-221–induced differentiation was determined using a two-way ANOVA with Bonferroni post-test corrections. *, P < 0.005 and **, P < 0.001. The AML-3 model was not included because it displayed very low levels of human cells in the blood; therefore, the effects of AG-221 on this parameter could not be assessed. B, hCD45 immunostaining (x100). In AG-221–treated mice, immunostaining revealed a dramatic decrease in hCD45+ cells in the BM (tibia). Representative samples from AML-2 shown. Scale bars, 100 μm. C, Cytology analysis of May-Grünwald-Giemsa–stained BM-derived cells illustrates the maturation of human blasts upon treatment with AG-221, as revealed by a decrease in the number of immature cells [blasts displaying cytoplasmic basophilia and high nucleocytoplasmic ratio (indicated by arrows on left plot)] accompanied by an increase in the number of more mature cell types such as myelocytes (black circles, right plot), metamyelocytes (black triangles, right plot), or neutrophils (black stars, right plot). Representative samples from AML-3 shown. Katharine Yen et al. Cancer Discov 2017;7:478-493 ©2017 by American Association for Cancer Research