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

J Biol Chem. 2016 Feb 26;291(9):4723-31. doi: 10.1074/jbc.M115.637835. Epub 2015 Dec 24.

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.

Keywords: B cell differentiation; BLNK; PAX5; PML; differentiation; leukemia; leukemia development; lymphocyte; oncogene; retrovirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Differentiation
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Down-Regulation
  • Humans
  • Leukemia, Experimental / metabolism*
  • Leukemia, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • PAX5 Transcription Factor / genetics
  • PAX5 Transcription Factor / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor Cells, B-Lymphoid / cytology
  • Precursor Cells, B-Lymphoid / metabolism*
  • Precursor Cells, B-Lymphoid / pathology
  • Promyelocytic Leukemia Protein
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Survival Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • PAX5 Transcription Factor
  • PAX5 protein, human
  • PAX5-PML fusion protein, human
  • Promyelocytic Leukemia Protein
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human