title: Direct activation of STAT5 by ETV6-LYN fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis.
abstract: Myeloproliferative neoplasms (MPN), a group of haematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the fusion of the ETV6 gene to the LYN gene (ETV6-LYN) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of ETV6-LYN into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged LYN kinase in the pathogenesis of MPN with myelofibrosis. However, the signalling molecules directly downstream from and activated by ETV6-LYN remain unknown. In this study, we demonstrated that the direct activation of STAT5 by ETV6-LYN is crucial for the development of MPN. ETV6-LYN was constitutively active as a kinase through autophosphorylation. ETV6-LYN, but not its kinase-dead mutant, supported cytokine-free proliferation of haematopoietic cells. STAT5 was activated in a JAK2-independent manner in ETV6-LYN-expressing cells. ETV6-LYN interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, ETV6-LYN did not support the formation of colonies by Stat5-deficient HSCs under cytokine-free conditions and the capacity of ETV6-LYN to induce MPN with myelofibrosis was profoundly attenuated in a Stat5-null background. These findings define STAT5 as a direct target of ETV6-LYN and unveil the LYN-STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukaemia.
authors.affiliation: Division of Haematology, Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takeda
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakaseko
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Makiko
authors.initials: M
authors.lastname: Yui
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.forename: Satomi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Chikako
authors.initials: C
authors.lastname: Ohwada
authors.forename: Emiko
authors.initials: E
authors.lastname: Sakaida
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009196:Myeloproliferative Disorders / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D055728:Primary Myelofibrosis / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D016207:Cytokines; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D019061:src-Family Kinases; D000097764:ETS Translocation Variant 6 Protein; C060902:lyn protein-tyrosine kinase