@entity817 inhibitors reverse the unique molecular signature and phenotype of XXXX and exert potent anti-leukemic activity.

@entity1 @entity8047 @entity5459 @entity706 @entity10043 @entity5734 @entity8553 @entity1074 @entity3963 @entity4910 @entity5458 @entity1892 @entity8554 @entity2902 @entity817 @entity5457
@entity5734 ( @entity8553 ) shows unique clinico-pathological and biological features. @entity8553 responds well to @entity10043 analogues but relapses are frequent and novel therapies are required. @entity817 - @entity8554 is the key driver mutation in @entity8553 and distinguishes it from other @entity1892 , including @entity706 ( @entity8553 -variant and @entity1074 ). The kinase-activating @entity817 - @entity8554 mutation also represents an ideal therapeutic target in @entity8553 . Here, we investigated the biological and therapeutic importance of the activated @entity817 - @entity8047 - @entity3963 pathway in @entity8553 by exposing in vitro primary leukemic cells purified from 26 @entity1 to clinically available @entity817 ( @entity5457 ; @entity5458 ) or @entity8047 ( @entity5459 ) inhibitors. Results were validated in vivo in samples from @entity5457 -treated @entity8553 @entity1 within a phase-2 clinical trial. @entity817 and @entity8047 inhibitors caused, specifically in @entity8553 (but not @entity8553 ) cells, marked @entity8047 / @entity3963 dephosphorylation, silencing of the @entity817 - @entity8047 - @entity3963 pathway transcriptional output, loss of the @entity8553 -specific gene expression signature, downregulation of the @entity8553 markers @entity2902 , TRAP and @entity4910 , smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing @entity8047 - @entity3963 dephosphorylation. This protective effect could be counteracted by combined @entity817 and @entity8047 inhibition. Our results strongly support and inform the clinical use of @entity817 and @entity8047 inhibitors in @entity8553 .
