Jak/Stat Pathway Mutations In T-All, Including The Stat5b N642h Mutation, Are Sensitive To Jak1/Jak3 Inhibitors

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive IL7R signaling is important for normal development, maturamalignancy of the lymphocytes that is driven by the cooperation of various mutations. Constitutive activation of JAK-STAT signaling is observed in one-third of T-ALL patients and is caused by activating mutations in the interleukin 7 receptor alpha chain (IL7R), in the Janus kinases JAK1 or JAK3, or in the Signal transducer and activator of transcription 5B (STAT5B). STAT5B mutations are most frequently the N642H variant and are associated with an unfavorable prognosis and higher risk of relapse. We set out to test the efficacy of JAK1/JAK3 kinase inhibitors ruxolitinib, tofacitinib, upadacitinib, baricitinib, decernotinib, and peficitinib in the murine Ba/F3 cell model transformed by different mutated components of JAK/STAT signaling.We show that cells carryingmutations in any component of IL7 receptor signaling are sensitive to JAK-inhibition, including mutations in STAT5B. JAK2 inhibition by ruxolitinib is a well-established treatment mechanism for polycythemia vera and myelofibrosis. The central role for the JAK1 and JAK3 kinases in IL7R/JAK/STAT driven T-ALL provides a rationale for JAK inhibition in this disease. The use of ruxolitinib, which has selectivity towards JAK1 and JAK2 and tofacitinib, targeting JAK1 and JAK3, in T-ALL is supported by preclinical evidence, showing sensitivity of IL7R, JAK1, and JAK3 mutated cases to these inhibitors in vitro and in vivo in patient-derived xenograft models. Indeed, mutant IL7R and mutant JAK3 typically require JAK1 activity and are sensitive to JAK1 inhibition. PhaseI/II clinical trials for acute lymphoblastic leukemia with ruxolitinib are currently ongoing.