C/EBPβ induces B-cell acute lymphoblastic leukemia and cooperates with BLNK mutations.
Morito KurataIichiro OnishiTomoko TakaharaYukari YamazakiSachiko IshibashiRyo GoitsukaDaisuke KitamuraJunko TakitaYasuhide HayashiDavid A LargaesapdaMasanobu KitagawaTakuro NakamuraPublished in: Cancer science (2021)
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.
Keyphrases
- acute lymphoblastic leukemia
- poor prognosis
- bone marrow
- binding protein
- endothelial cells
- gene expression
- acute myeloid leukemia
- allogeneic hematopoietic stem cell transplantation
- tyrosine kinase
- mesenchymal stem cells
- risk factors
- signaling pathway
- adipose tissue
- metabolic syndrome
- genome wide
- high glucose
- oxidative stress
- chronic myeloid leukemia
- nuclear factor
- heat stress
- network analysis
- heat shock
- toll like receptor