PuSH - Publikationsserver des Helmholtz Zentrums München: Azacitidine combined with the selective FLT3 kinase inhibitor crenolanib disrupts stromal protection and inhibits expansion of residual leukemia-initiating cells in FLT3-ITD AML with concurrent epigenetic mutations.

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Garz, A.K.* ; Wolf, S.* ; Grath, S.* ; Gaidzik, V.I.* ; Habringer, S.* ; Vick, B. ; Rudelius, M.* ; Ziegenhain, C.* ; Herold, S.* ; Weickert, M.T.* ; Smets, M.* ; Peschel, C.* ; Oostendorp, R.A.J.* ; Bultmann, S.* ; Jeremias, I. ; Thiede, C.* ; Döhner, K.* ; Keller, U.* ; Götze, K.S.*

Azacitidine combined with the selective FLT3 kinase inhibitor crenolanib disrupts stromal protection and inhibits expansion of residual leukemia-initiating cells in FLT3-ITD AML with concurrent epigenetic mutations.

Oncotarget 8, 108738-108759 (2017)

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Effectively targeting leukemia-initiating cells (LIC) in FLT3-ITD-mutated acute myeloid leukemia (AML) is crucial for cure. Tyrosine kinase inhibitors (TKI) have limited impact as single agents, failing to eradicate LIC in the bone marrow. Using primary AML samples and a patient-derived xenograft model, we investigated whether combining the FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) eliminates FLT3-ITD LIC and whether efficacy of this combination depends on co-existing mutations. Using multiparameter flow cytometry, we show FLT3-ITD occurs within the most primitive Lin(-)/CD33((+))/CD45(dim)/CD34(+) CD38(-) LIC compartment. Crenolanib alone could not target FLT3-ITD LIC in contact with niche cells while addition of AZA overcame stromal protection resulting in dramatically reduced clonogenic capacity of LIC in vitro and severely impaired engraftment in NSG mice. Strikingly, FLT3-mutated samples harboring TET2 mutations were completely resistant to crenolanib whereas neither NPM1 nor DNMT3A mutations influenced response. Conversely, primary AML LIC harboring either TET2, DNMT3A or NPM1 mutations did not show increased sensitivity to AZA. In summary, resistance of FLT3-ITD LIC to TKI depends on co-existing epigenetic mutations. However, AZA + crenolanib effectively abrogates stromal protection and inhibits survival of FLT3-ITD LIC irrespective of mutations, providing evidence for this combination as a means to suppress residual LIC.

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