B cell linker protein (BLNK) is a selective target of repression by PAX5-PML protein in the differentiation block that leads to the development of acute lymphoblastic leukemia

Naoto Imoto, Fumihiko Hayakawa, Shingo Kurahashi, Takanobu Morishita, Yuki Kojima, Takahiko Yasuda, Keiki Sugimoto, Shinobu Tsuzuki, Tomoki Naoe, Hitoshi Kiyoi

研究成果: ジャーナルへの寄稿学術論文査読

18 被引用数 (Scopus)

抄録

PAX5 is a transcription factor that is required for the development and maintenance of B cells. Promyelocytic leukemia (PML) is a tumor suppressor and proapoptotic factor. The fusion gene PAX5-PML has been identified in acute lymphoblastic leukemia with chromosomal translocation t(9;15)(p13; q24). We have reported previously that PAX5-PML dominant negatively inhibited PAX5 transcriptional activity and impaired PML function bydisrupting PML nuclear bodies (NBs). Here we demonstrated the leukemogenicity of PAX5-PML by introducing it into normal mouse pro-B cells. Arrest of differentiation was observedin PAX5-PML-introduced pro-B cells, resulting in the development of acute lymphoblastic leukemia after a long latency in mice. Among the transactivation targets of PAX5, B cell linker protein (BLNK) was repressed selectively in leukemia cells, and enforced BLNK expression abrogated the differentiation block and survival induced by PAX5-PML, indicating the importance of BLNK repression for the formation of preleukemic state. We also showed that PML NBs were intactinleukemia cells and attributed this to the low expression of PAX5-PML, indicating that the disruption of PML NBs was not required for the PAX5-PML-induced onset of leukemia. These results provide novel insights into the molecular mechanisms underlying the onset of leukemia by PAX5 mutations.

本文言語英語
ページ(範囲)4723-4731
ページ数9
ジャーナルJournal of Biological Chemistry
291
9
DOI
出版ステータス出版済み - 26-02-2016
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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