Intrinsic resistance to JAK2 inhibition in myelofibrosis
Menée in vitro, cette étude met en évidence des mécanismes de résistance à un traitement par inhibiteur de JAK2 dans les myélofibroses
Purpose: Recent results have demonstrated that myeloproliferative neoplasms (MPN) are strongly associated with constitutive activation of the JAK2 tyrosine kinase. However, JAK2 inhibitors currently approved or under development for treating myeloproliferative neoplasms do not selectively deplete the malignant clone, and the inhibition of activity of the drug target (JAK2) has not been rigorously evaluated in clinical studies. Therefore in this study we developed an in vitro assay to gain insight into how effectively JAK2 activity is inhibited in patient samples. Experimental Design: We treated primary cells from normal donors and patients with MPN with JAK2 inhibitors and measured phosphorylation of downstream targets STAT5 and STAT3 by flow cytometry. Obtained results were next correlated with JAK2 V617F allele burden and plasma cytokines level. Results: We observed a dose-dependent decrease in pSTAT5 and pSTAT3 in ex vivo treated granulocytes. However, phosphorylation of STAT3 and STAT5 in cells from patients with myelofibrosis was significantly less inhibited when compared to cells from patients with polycythemia vera, essential thrombocytosis, and normal donors. Sensitivity to inhibition did not correlate with JAK2 V617F clonal burden. Mixing studies using plasma from patients with myelofibrosis did not transfer resistance to sensitive cells. Likewise, no single cytokine measured appeared to account for the observed pattern of resistance. Conclusions: Taken together these observations suggest that there are cell intrinsic mechanisms that define a priori resistance to JAK2 inhibition in myelofibrosis, and the lesion is localized upstream of STAT3 and STAT5.