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| Status |
Public on Dec 19, 2017 |
| Title |
Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival below 20%. We observed that sorafenib increased IL-15 production by FLT3-ITD+-leukemia cells, which synergized with the allogeneic CD8+T-cell response, leading to long-term survival in murine and humanized FLT3-ITD+AML models. Using IL-15 deficiency in recipient tissues or leukemia cells, IL-15 production upon sorafenib-treatment could be attributed to leukemia cells. Sorafenib treatment-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T-cells with features of longevity (Bcl-2high/reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced ATF4 expression, thereby blocking negative regulation of IRF7-activation, which enhances IL-15 transcription. Consistent with the mouse data, IL-15 and pIRF7 levels increased in leukemic blasts of FLT3-ITD+AML patients upon sorafenib treatment. Analysis of 130 patients with FLT3-ITD-mutant AML relapsing after allo-HCT showed the highest complete remission-rate and median overall-survival-rate in the sorafenib/donor lymphocyte infusion (DLI) group compared to all other groups (chemotherapy, chemotherapy/DLI, sorafenib alone). Our findings indicate that the synergism of DLI and sorafenib is mediated via reduced ATF4 expression, causing activation of the pIRF7/IL-15-axis in leukemia cells. The sorafenib/DLI strategy therefore has the potential for an immune-mediated cure of FLT3-ITD-mutant AML- relapse, an otherwise fatal complication after allo-HCT.
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| Overall design |
Peripheral blood mononuclear cells (PBMC) from patients relapsing after allograft transplantation were extracted three days before and six days after treatment with sorafenib. 4 patients, marked as responders, showed a favorable outcome event after 6 months, while 4 patients. marked as non-responders. did not respond to sorafenib treatment.
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| Contributor(s) |
Busch H, Boerries M, Zeiser R, Pfeifer D, Dunesque S |
| Citation(s) |
29431743 |
| |
| Submission date |
Mar 07, 2017 |
| Last update date |
Feb 01, 2019 |
| Contact name |
Hauke Busch |
| E-mail(s) |
hauke.busch@uni-luebeck.de
|
| Phone |
+49-451-3101-8470
|
| Organization name |
University of Lübeck
|
| Department |
Lübeck Institute of Experimental Dermatology
|
| Street address |
Ratzeburger Allee 160
|
| City |
Lübeck |
| State/province |
Schleswig-Holstein |
| ZIP/Postal code |
23538 |
| Country |
Germany |
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| Platforms (1) |
| GPL23159 |
[Clariom_S_Human] Affymetrix Clariom S Assay, Human (Includes Pico Assay) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA378360 |
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