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Direct activation of STAT5 by ETV6‐LYN fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis
Author(s) -
Takeda Yusuke,
Nakaseko Chiaki,
Tanaka Hiroaki,
Takeuchi Masahiro,
Yui Makiko,
Saraya Atsunori,
Miyagi Satoru,
Wang Changshan,
Tanaka Satomi,
Ohwada Chikako,
Sakaida Emiko,
Yamaguchi Naoto,
Yokote Koutaro,
Hennighausen Lothar,
Iwama Atsushi
Publication year - 2011
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2011.08663.x
Subject(s) - lyn , myelofibrosis , stat5 , cancer research , dasatinib , haematopoiesis , myeloproliferative neoplasm , biology , medicine , stem cell , immunology , signal transduction , tyrosine kinase , microbiology and biotechnology , imatinib , myeloid leukemia , bone marrow
Summary 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.