tofacitinib and Cell-Transformation--Neoplastic

T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in

Topics: Aged; Cell Transformation, Neoplastic; DEAD-box RNA Helicases; Drug Resistance, Neoplasm; Exome Sequencing; Female; Humans; Janus Kinase 1; Janus Kinase 3; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Transcription Factors

JAK3 is a tyrosine kinase that associates with the common γ chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cells in a Jak1 kinase-independent manner. Reconstitution of the IL7 receptor signaling complex in 293T cells showed that JAK3 mutants required receptor binding to mediate downstream STAT5 phosphorylation. Mice transplanted with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-ALL-like disease, characterized by an accumulation of immature CD8(+) T cells. In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white blood cell count and caused leukemic cell apoptosis. Our data show that JAK3 mutations are drivers of T-ALL and require the cytokine receptor complex for transformation. These results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL.

Topics: Acute Disease; Animals; Cell Transformation, Neoplastic; Disease Models, Animal; Enzyme Activation; Janus Kinase 1; Janus Kinase 3; Leukemia, T-Cell; Male; Mice; Mice, Inbred BALB C; Mutation; Piperidines; Pyrimidines; Pyrroles; Signal Transduction; T-Lymphocytes