JAK1 and TYK2 activate JAK2 in trans to promote JAK-STAT signaling despite chronic JAK2 inhibition.

  • Major finding: JAK1 and TYK2 activate JAK2 in trans to promote JAK-STAT signaling despite chronic JAK2 inhibition.

  • Clinical relevance: MPN cells become resensitized to JAK2 kinase inhibitors after inhibitor withdrawal.

  • Impact: Therapies that promote JAK2 degradation or target inactive JAK2 may be effective in MPN.

Most myeloproliferative neoplasms (MPN) harbor somatic activating mutations in Janus kinase 2 (JAK2). JAK2 kinase inhibitor therapy alleviates some symptoms associated with MPN but does not significantly decrease disease burden in most patients. To identify possible mechanisms of JAK2 inhibitor resistance in MPN, Koppikar and colleagues first sequenced JAK2 in MPN cells exposed to JAK2 kinase inhibitors in vitro and granulocytes from JAK2 inhibitor-treated patients with MPN. Less than half of cells exposed to JAK2 inhibitors and none of the treated MPN patients acquired secondary JAK2 mutations. Despite chronic JAK2 kinase inhibition, JAK2-mutant cells became tolerant of multiple JAK2 inhibitors through reactivation of JAK2 and downstream JAK-STAT target genes. The related JAK family kinases JAK1 and tyrosine kinase 2 (TYK2) were also activated and physically interacted with phosphorylated JAK2 in inhibitor-treated patient samples. Importantly, the kinase activity of these heterodimer complexes could maintain JAK2 phosphorylation at inhibitor concentrations that blocked JAK2 autophosphorylation. Additionally, in response to prolonged JAK2 inhibitor treatment, JAK2 mRNA levels increased and activated JAK2 was stabilized, which could facilitate heterodimer formation. Drug-tolerant cells could be resensitized to several different JAK2 inhibitors by inhibitor withdrawal, which abrogated the interaction between JAK2 and JAK1 or TYK2 and decreased activated JAK2 levels. Persistent cells were also still dependent on JAK2 and thus were sensitive to therapies that promoted JAK2 degradation or stabilized the inactive form of JAK2. Together, these findings provide an explanation for the inability of JAK2 kinase inhibitors to reduce disease burden in MPN cells and suggest that alternative methods of JAK2 inhibition may have greater clinical efficacy.

Koppikar P, Bhagwat N, Klipivaara O, Manshouri T, Adli M, Hricik T, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature 2012 July 22 [Epub ahead of print].