Abstract
Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-3 + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.
Original language | English |
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Pages (from-to) | 282-291 |
Number of pages | 10 |
Journal | Nature Medicine |
Volume | 24 |
Issue number | 3 |
Early online date | 12 Feb 2018 |
DOIs | |
Publication status | Published - Mar 2018 |
Keywords
- Activating Transcription Factor 4/genetics
- Animals
- CD8-Positive T-Lymphocytes/immunology
- Cellular Reprogramming/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Graft vs Host Disease/drug therapy
- Hematopoietic Stem Cell Transplantation/adverse effects
- Humans
- Interferon Regulatory Factor-7/genetics
- Interleukin-15/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Mice
- Sorafenib/administration & dosage
- Tandem Repeat Sequences/genetics
- Transplantation, Homologous/adverse effects
- fms-Like Tyrosine Kinase 3/genetics