Mechanism of myelofibrosis by a novel TEL-Lyn fusion gene.

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: NAKASEKO Chiaki Chiba University, 大学院・医学研究院, 講師 (30323398)
• Project Period (FY): 2008 – 2010
• Keywords: 血液腫瘍学 / 慢性骨髄増殖性疾患 / 骨髄線維症 / TEL-Lyn / チロシンキナーゼ阻害剤 / 白血病 / STAT5

Research Abstract

Myeloproliferative neoplasms (MPN), a group of hematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the TEL-Lyn fusion gene in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of TEL-Lyn into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged Lyn kinase in the pathogenesis of MPN with myelofibrosis. In this study, we demonstrated that the direct activation of STAT5 by TEL-Lyn is crucial for the development of MPN. TEL-Lyn was constitutively active as a kinase through autophosphorylation. In TEL-Lyn-expressing cells, STAT5 was activated in a JAK2-independent manner. TEL-Lyn interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, TEL-Lyn did not support the formation of colonies by Stat5-deficient HSCs under cytokine-free conditions and the capacity of TEL-Lyn to induce MPN with myelofibrosis was profoundly attenuated in a Stat5-null background. These findings define STAT5 as a direct target of TEL-Lyn and unveil the Lyn-STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukemia.

Research Products

• [Journal Article] Takeda Y, Nakaseko C, Tanaka H, Takeuchi M, Yui M, Saraya A, Miyagi S, Ohwada C, Sakaida E, Yamaguchi N, Yokote K, Hennighausen L, Iwama A. (2011)
  • Author(s): Takeda Y, Nakaseko C, Tanaka H, Takeuchi M, Yui M, Saraya A, Miyagi S, Ohwada C, Sakaida E, Yamaguchi N, Yokote K, Hennighausen L, Iwama A.
  • Journal Title: Brit J Haematol [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Identification of a novel TEL-Lyn fusion gene in primary myelofibrosis. (2010)
  • Author(s): Tanaka H, Takeuchi M, Takeda Y, Sakai S, Abe D, Ohwada C, Sakaida E, Shimizu N, Saito Y, Miyagi S, Iwama A, Nakaseko C.
  • Journal Title: Leukemia 24(1) Pages: 197-200
  • Peer Reviewed
• [Journal Article] Clonal expansion of non-leukemic cells expressing two novel MLL-ELL variants with distinct transforming activity. (2008)
  • Author(s): Takeuchi M, Nakaseko C, Miyagi S, Takeda Y, Ozawa S, Ohwada C, Cho R, Nishimura M, Saito Y, Iwama A.
  • Journal Title: Leukemia 22(4) Pages: 861-864
  • Peer Reviewed
• [Presentation] Direct Activation of STAT5 by TEL-Lyn Fusion Protein Promotes Induction of Myeloproliferative Neoplasms with Myelofibrosis. (2010)
  • Author(s): 竹田勇輔, 中世古知昭, 田中宏明, 武内正博, 由井麻紀子, 更家敦則, 宮城聡, 大和田千桂子, 堺田恵美子, 横手幸太郎, 岩間厚志
  • Organizer: The 52th American Society of Hematology
  • Place of Presentation: Orlando
  • Year and Date: 2010-12-07
• [Presentation] TEL-Lyn融合タンパクはStat5を活性化し骨髄線維症を誘発する (2010)
  • Author(s): 竹田勇輔, 中世古知昭, 田中宏明, 武内正博, 由井麻紀子, 更家敦則, 宮城聡, 大和田千桂子, 堺田恵美子, 山口直人, 横手幸太郎, Lothar Hennighausen, 岩間厚志
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Remarks] ホームページ等
  • URL: http://www.m.chiba-u.ac.jp/class/hematology/