Dataset Information


Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia.

ABSTRACT: Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile, as well as a high rate of induction failure. Frequent mutations in cytokine receptor and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to interleukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pretreatment levels and compared with control (P < .01) in 5 of 6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P < .01) in 6 of 6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed.


PROVIDER: S-EPMC4357583 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

| EGAS00001001146 | EGA
1000-01-01 | S-EPMC3482861 | BioStudies
2017-01-01 | S-EPMC5729333 | BioStudies
2014-01-01 | S-EPMC3978278 | BioStudies
2020-01-01 | S-EPMC7305753 | BioStudies
2017-01-01 | S-EPMC5384417 | BioStudies
2020-01-01 | S-EPMC7375176 | BioStudies
2014-01-01 | S-EPMC3968390 | BioStudies
2020-01-01 | S-EPMC7917252 | BioStudies
2019-01-01 | S-EPMC6841977 | BioStudies