C/EBPβ induces B-cell acute lymphoblastic leukemia and cooperates with BLNK mutations

Cancer Sci. 2021 Dec;112(12):4920-4930. doi: 10.1111/cas.15164. Epub 2021 Oct 23.


BLNK (BASH/SLP-65) encodes an adaptor protein that plays an important role in B-cell receptor (BCR) signaling. Loss-of-function mutations in this gene are observed in human pre-B acute lymphoblastic leukemia (ALL), and a subset of Blnk knock-out (KO) mice develop pre-B-ALL. To understand the molecular mechanism of the Blnk mutation-associated pre-B-ALL development, retroviral tagging was applied to KO mice using the Moloney murine leukemia virus (MoMLV). The Blnk mutation that significantly accelerated the onset of MoMLV-induced leukemia and increased the incidence of pre-B-ALL Cebpb was identified as a frequent site of retroviral integration, suggesting that its upregulation cooperates with Blnk mutations. Transgenic expression of the liver-enriched activator protein (LAP) isoform of Cebpb reduced the number of mature B-lymphocytes in the bone marrow and inhibited differentiation at the pre-BI stage. Furthermore, LAP expression significantly accelerated leukemogenesis in Blnk KO mice and alone acted as a B-cell oncogene. Furthermore, an inverse relationship between BLNK and C/EBPβ expression was also noted in human pre-B-ALL cases, and the high level of CEBPB expression was associated with short survival periods in patients with BLNK-downregulated pre-B-ALL. These results indicate the association between the C/EBPβ transcriptional network and BCR signaling in pre-B-ALL development and leukemogenesis. This study gives insight into ALL progression and suggests that the BCR/C/EBPβ pathway can be a therapeutic target.

Keywords: B-cell receptor; BLNK; C/EBPβ; acute lymphoblastic leukemia; retroviral tagging.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Moloney murine leukemia virus / physiology*
  • Mutation*
  • Oligonucleotide Array Sequence Analysis
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / virology
  • Up-Regulation
  • Virus Integration


  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • CCAAT-Enhancer-Binding Protein-beta
  • CEBPB protein, human