BCR-ABL affects STAT5A and STAT5B differentially.
Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors linking extracellular signals to target gene transcription. Hematopoietic cells express two highly conserved STAT5-isoforms (STAT5A/STAT5B), and STAT5 is directly activated by JAK2 downstream of several cytokine receptors and the oncogenic BCR-ABL tyrosine kinase. Using an IL-3-dependent cell line with inducible BCR-ABL-expression we compared STAT5-activation by IL-3 and BCR-ABL in a STAT5-isoform specific manner. RNAi targeting of STAT5B strongly inhibits BCR-ABL-dependent cell proliferation, and STAT5B but not STAT5A is essential for BCL-XL-expression in the presence of BCR-ABL. Although BCR-ABL induces STAT5-tyrosine phosphorylation independent of JAK2-kinase activity, BCR-ABL is less efficient in inducing active STAT5A:STAT5B-heterodimerization than IL-3, leaving constitutive STAT5A and STAT5B-homodimerization unaffected. In comparison to IL-3, nuclear accumulation of a STAT5A-eGFP fusion protein is reduced by BCR-ABL, and BCR-ABL tyrosine kinase activity induces STAT5A-eGFP translocation to the cell membrane and co-localization with the IL-3 receptor. Furthermore, BCR-ABL-dependent phosphorylation of Y682 in STAT5A was detected by mass-spectrometry. Finally, RNAi targeting STAT5B but not STAT5A sensitizes human BCR-ABL-positive cell lines to imatinib-treatment. These data demonstrate differences between IL-3 and BCR-ABL-mediated STAT5-activation and isoform-specific effects, indicating therapeutic options for isoform-specific STAT5-inhibition in BCR-ABL-positive leukemia.
Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany.
Michael
M
Schaller-Schönitz
Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany.
David
D
Barzan
Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Wolfson Molecular Imaging Centre, Manchester, United Kingdom.
Andrew J K
AJ
Williamson
Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Wolfson Molecular Imaging Centre, Manchester, United Kingdom.
John R
JR
Griffiths
Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany.
Iris
I
Dallmann
Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany.
Karin
K
Battmer
Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany.
Arnold
A
Ganser
Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Wolfson Molecular Imaging Centre, Manchester, United Kingdom.
Anthony D
AD
Whetton
Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany.
Michaela
M
Scherr
Hannover Medical School, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany.
Matthias
M
Eder
D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D019281:Dimerization; D005455:Fluorescent Antibody Technique; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D047468:Immunoprecipitation; D007377:Interleukin-3 / Q000378:metabolism; D016086:Lentivirus; D013058:Mass Spectrometry; D010766:Phosphorylation; D010879:Piperazines; D011743:Pyrimidines; D034622:RNA Interference; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D001549:Benzamides; D007377:Interleukin-3; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl