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. PML is a tumor suppressor and pro-apoptotic factor. The fusion gene, PAX5-PML, has been identified in acute lymphoblastic leukemia (ALL) with chromosomal translocation t(9;15)(p13;q24). We previously reported that PAX5-PML dominant-negatively inhibited PAX5 transcriptional activity and impaired PML function by disrupting PML nuclear bodies (NBs). We herein demonstrated the leukemogenicity of PAX5-PML by introducing it into normal mouse pro B cells. The arrest of differentiation was observed in PAX5-PML-introduced pro B cells, resulting in the development of ALL after a long latency in mice. Among the transactivation targets of PAX5, BLNK was selectively repressed in leukemia cells and enforced BLNK expression abrogated differentiation block induced by PAX5-PML, indicating the importance of BLNK repression for the differentiation block. 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.