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Int J Cancer. 2019 Sep 15;145(6):1558-1569. doi: 10.1002/ijc.32246. Epub 2019 Mar 23.

Targeting RIPK1 in AML cells carrying FLT3-ITD.

Author information

1
Translational Inflammation Research, Health Campus Immunology, Infectiology and Inflammation, Center of Dynamic Systems, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
2
Department of Hematology and Oncology, Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Medical Faculty, Magdeburg, Germany.
3
Institute of Experimental Internal Medicine, Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Medical Faculty, Magdeburg, Germany.

Abstract

Mutations of fms-like tyrosine kinase 3 (FLT3) are the most frequent mutations in acute myeloid leukemia (AML). Furthermore, the internal tandem duplication (ITD) represents the most common mutation of FLT3 in AML. To explore therapeutic strategies for AML patients carrying FLT3-ITD, we analyzed death receptor (DR) signaling networks in AML cells comprising FLT3-ITD. We have started with murine myeloid progenitor 32D cells that ectopically express human FLT3-ITD (32D- FLT3-ITD) and found that RIPK1 is strongly upregulated in these cells. Subsequently, we have shown that combinatorial treatment of 32D-FLT3-ITD cells with the SMAC mimetic BV6 and CD95L sensitizes these cells toward apoptosis and necroptosis. Moreover, combinatorial treatment with death ligands (DLs), for example, CD95L or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and BV6 enhanced cell death in primary AML blasts from patients carrying FLT3-ITD mutation. Finally, pharmacological and genetic targeting of RIPK1 inhibited DL/BV6-mediated cell death in cells with FLT3-ITD mutations. Taken together, our study suggests a promising therapeutic opportunity for AML cancer cells harboring FLT3-ITD mutation via targeting RIPK1 pathways.

KEYWORDS:

AML; FLT3-ITD; RIPK1; cell death; death receptor

PMID:
30828789
DOI:
10.1002/ijc.32246

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