RESUMEN
The identification of somatic activating mutations in JAK2 (refs 14) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAKSTAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.
Asunto(s)
Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Trastornos Mieloproliferativos/tratamiento farmacológico , Multimerización de Proteína , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Animales , Línea Celular , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Granulocitos/efectos de los fármacos , Granulocitos/enzimología , Granulocitos/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Janus Quinasa 1/biosíntesis , Janus Quinasa 1/deficiencia , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Janus Quinasa 2/deficiencia , Janus Quinasa 2/genética , Ratones , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Fosforilación , Biosíntesis de Proteínas , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , TYK2 Quinasa/biosíntesis , TYK2 Quinasa/deficiencia , TYK2 Quinasa/genética , TYK2 Quinasa/metabolismoRESUMEN
BACKGROUND: We established multiple University of Michigan Squamous Cell Carcinoma (UM-SCC) cell lines. With time, these have been distributed to other labs all over the world. Recent scientific discussions have noted the need to confirm the origin and identity of cell lines in grant proposals and journal articles. We genotyped the UM-SCC cell lines in our collection to confirm their unique identity. METHOD: Early-passage UM-SCC cell lines were genotyped and photographed. RESULTS: Thus far, 73 unique head and neck UM-SCC cell lines (from 65 donors, including 21 lines from 17 females) were genotyped. In 7 cases, separate cell lines were established from the same donor. CONCLUSIONS: These results will be posted on the UM Head and Neck SPORE Tissue Core website for other investigators to confirm that the UM-SCC cells used in their laboratories have the correct features. Publications using UM-SCC cell lines should confirm the genotype.