GSE96048
JAK dependent survival of ALK- ALCL
Activating JAK and STAT mutations were discovered in many T-cell malignancies including ALK- anaplastic large cell lymphomas (ALCL). However, such mutations often occur in a minority of patients. To investigate the clinical application of targeting Janus Kinase (JAK) for ALK- ALCL, we treated ALK- cell lines of different histologic origins with JAK inhibitors. Interestingly, most exogenous cytokine independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with STAT3 phosphorylation status of tumor cells. Employing retroviral shRNA knockdown, we demonstrated that these JAK inhibitor sensitive cells were dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some but not all JAK inhibitor sensitive cells. Moreover, the mutations alone could not explain the JAK1/STAT3 dependency as wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2R?. Knockdown of GP130 or IL-2R? induced cell death in select JAK inhibitor sensitive cells. High levels of cytokine expression including IL-6 were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest cytokine receptor signaling was required for tumor cell survival in diverse forms of ALK- ALCL even in the presence of JAK1/STAT3 mutations. Therefore, JAK-inhibitor therapy might benefit patients with ALK- ALCL that are pSTAT3+. Overall design: We performed RNA-seq to examine whether JAK and STAT genes were mutated in these JAK inhibitor sensitive ALK-ALCL cell lines: Mac-1, Mac-2A, Mac-2B, Fe-Pd, TLBR1, and TLBR2,(n=6). pSTAT3 negative ALK-ALCL cell lines DL40 and TLBR3 (n=2) (also JAK inhibitor insensitive) were used as negative cell controls. All ALK- cell lines grew independent of exogenous cytokines with the exception of TLBR4, which needed exogenous IL-2 to grow.