Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

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-γ⁺ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechani

SUBMITTER: Mathew NR 

PROVIDER: S-EPMC6029618 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature