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Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk  JAK2 -rearranged ( JAK2 r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in  JAK2 r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model of  ATF7IP-JAK2  with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within the  JAK2  ATP/rux binding site, including a  JAK2  p.G993A mutation. Using in vitro models of  JAK2 r B-ALL,  JAK2  p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that  JAK2  p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.

Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia