Chatterjee, AnindyaGhosh, JoydeepRamdas, BaskarMali, Raghuveer SinghMartin, HollyKobayashi, MichihiroVemula, SasidharCanela, Victor H.Waskow, Emily R.Visconte, ValeriaTiu, Ramon V.Smith, Catherine C.Shah, NeilBunting, Kevin D.Boswell, H. ScottLiu, YanChan, Rebecca J.Kapur, Reuben2016-03-042016-03-042014-11-20Chatterjee, A., Ghosh, J., Ramdas, B., Mali, R. S., Martin, H., Kobayashi, M., … Kapur, R. (2014). Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3 and KIT driven Leukemogenesis. Cell Reports, 9(4), 1333–1348. http://doi.org/10.1016/j.celrep.2014.10.039https://hdl.handle.net/1805/8703Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK), whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.en-USPublisher PolicyAnimalsBenzothiazolesCarcinogenesisCell NucleusCell ProliferationFocal Adhesion Protein-Tyrosine KinasesGuanine Nucleotide Exchange FactorsHumansLeukemia, Myeloid, AcuteMastocytosis, SystemicMice, Inbred C57BLMutant ProteinsMutationPhenylurea CompoundsPhosphorylationProtein Kinase InhibitorProtein TransportProto-Oncogene Proteins c-kitSTAT5 Transcription FactorSignal TransductionSurvival Analysisfms-Like Tyrosine Kinase 3p21-Activated Kinasesrac1 GTP-Binding ProteinArticle