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Series GSE95770 Query DataSets for GSE95770
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
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.
 
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.
 
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
 
Platforms (1)
GPL23159 [Clariom_S_Human] Affymetrix Clariom S Assay, Human (Includes Pico Assay)
Samples (16)
GSM2525642 PBMC_Responder_Patient1_-3d
GSM2525643 PBMC_Responder_Patient1_6d
GSM2525644 PBMC_Responder_Patient2_-3d
Relations
BioProject PRJNA378360

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE95770_RAW.tar 18.1 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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