Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors.

ABSTRACT:

Background

Activating mutations in JAK1 and JAK2 have been described in patients with various hematologic malignancies including acute lymphoblastic leukemia and myeloproliferative neoplasms, leading to clinical trials with JAK inhibitors. While there has been a tremendous effort towards the development of specific JAK inhibitors, mutations conferring resistance to such drugs have not yet been observed.

Design and methods

Taking advantage of a model of spontaneous cellular transformation, we sequenced JAK1 in selected tumorigenic BaF3 clones and identified 25 de novo JAK1 activating mutations, including 5 mutations already described in human leukemias. We further used this library of JAK1 mutation-positive cell lines to assess their sensitivity to ATP-competitive inhibitors.

SUBMITTER: Hornakova T 

PROVIDER: S-EPMC3105646 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature