Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis
Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-11-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714009085 |
| _version_ | 1819131068463185920 |
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| author | Anindya Chatterjee Joydeep Ghosh Baskar Ramdas Raghuveer Singh Mali Holly Martin Michihiro Kobayashi Sasidhar Vemula Victor H. Canela Emily R. Waskow Valeria Visconte Ramon V. Tiu Catherine C. Smith Neil Shah Kevin D. Bunting H. Scott Boswell Yan Liu Rebecca J. Chan Reuben Kapur |
| author_facet | Anindya Chatterjee Joydeep Ghosh Baskar Ramdas Raghuveer Singh Mali Holly Martin Michihiro Kobayashi Sasidhar Vemula Victor H. Canela Emily R. Waskow Valeria Visconte Ramon V. Tiu Catherine C. Smith Neil Shah Kevin D. Bunting H. Scott Boswell Yan Liu Rebecca J. Chan Reuben Kapur |
| author_sort | Anindya Chatterjee |
| collection | DOAJ |
| description | Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), 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. |
| first_indexed | 2024-12-22T09:09:38Z |
| format | Article |
| id | doaj.art-3fb0e4f417624b859de3a4859396cf8a |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T09:09:38Z |
| publishDate | 2014-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3fb0e4f417624b859de3a4859396cf8a2022-12-21T18:31:29ZengElsevierCell Reports2211-12472014-11-01941333134810.1016/j.celrep.2014.10.039Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven LeukemogenesisAnindya Chatterjee0Joydeep Ghosh1Baskar Ramdas2Raghuveer Singh Mali3Holly Martin4Michihiro Kobayashi5Sasidhar Vemula6Victor H. Canela7Emily R. Waskow8Valeria Visconte9Ramon V. Tiu10Catherine C. Smith11Neil Shah12Kevin D. Bunting13H. Scott Boswell14Yan Liu15Rebecca J. Chan16Reuben Kapur17Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USADivision of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USADivision of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USADepartment of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USADivision of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USAOncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), 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.http://www.sciencedirect.com/science/article/pii/S2211124714009085 |
| spellingShingle | Anindya Chatterjee Joydeep Ghosh Baskar Ramdas Raghuveer Singh Mali Holly Martin Michihiro Kobayashi Sasidhar Vemula Victor H. Canela Emily R. Waskow Valeria Visconte Ramon V. Tiu Catherine C. Smith Neil Shah Kevin D. Bunting H. Scott Boswell Yan Liu Rebecca J. Chan Reuben Kapur Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis Cell Reports |
| title | Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis |
| title_full | Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis |
| title_fullStr | Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis |
| title_full_unstemmed | Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis |
| title_short | Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis |
| title_sort | regulation of stat5 by fak and pak1 in oncogenic flt3 and kit driven leukemogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714009085 |
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