American Association for Cancer Research
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Figure S5 from The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

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journal contribution
posted on 2023-04-03, 15:43 authored by Maximilien Murone, Ramin Radpour, Antoine Attinger, Anne Vaslin Chessex, Anne-Laure Huguenin, Christian M. Schürch, Yara Banz, Saumitra Sengupta, Michel Aguet, Stefania Rigotti, Yogeshwar Bachhav, Frédéric Massière, Murali Ramachandra, Andres McAllister, Carsten Riether

Figure S5 shows the anti-leukemic activity of Debio 0617B in a MOLM-13-luciferase disseminated AML mouse model.





Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34+ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497–510. ©2017 AACR.

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