title: 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.
abstract: 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 by disrupting 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 observed in 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 intact in leukemia 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.
authors.affiliation: From the Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Imoto
authors.affiliation: From the Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan, bun-hy@med.nagoya-u.ac.jp.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.affiliation: the Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, 441-8570, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kurahashi
authors.affiliation: From the Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Morishita
authors.affiliation: From the Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: the Department of Cellular Signaling, Graduate School of Medicine, University of Tokyo, 113-8654, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: the Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, 520-0106, Japan.
authors.forename: Keiki
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: the Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan, and.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.affiliation: the National Hospital Organization Nagoya Medical Center, Nagoya, 460-0001, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.affiliation: From the Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007942:Leukemia, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D000071156:Promyelocytic Leukemia Protein; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C000609420:PAX5-PML fusion protein, human; D000071156:Promyelocytic Leukemia Protein; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human
keywords: B cell differentiation; BLNK; PAX5; PML; differentiation; leukemia; leukemia development; lymphocyte; oncogene; retrovirus