Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms.

ABSTRACT: The discovery of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of Janus kinase (JAK) inhibitors for treatment of MPN. These inhibitors improve constitutional symptoms and splenomegaly but do not significantly reduce mutant allele burden in patients. We recently showed that chronic exposure to JAK inhibitors results in inhibitor persistence via JAK2 transactivation and persistent JAK-signal transducer and activator of transcription signaling. We performed genetic and pharmacologic studies to determine whether improved JAK2 inhibition would show increased efficacy in MPN models and primary samples. Jak2 deletion in vivo led to profound reduction in disease burden not seen with JAK inhibitors, and deletion of Jak2 following chronic ruxoliti

SUBMITTER: Bhagwat N 

PROVIDER: S-EPMC3968390 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature