PAX5-PML Induces Pro B Acute Lymphoblastic Leukemia in Mice

PAX5 is a transcription factor required for B-cell development and maintenance. We previously showed that PAX5-PML, a fusion gene found in acute lymphoblastic leukemia (ALL), dominant negatively inhibited PAX5 transcriptional activity. Reported data including ours revealed that PAX5 fusion proteins had possible oncogenic ability; however, leukemogenicity of PAX5 fusion genes and other PAX5 mutations in mice model has not been clarified, yet. Here we demonstrated leukemia development in mice by introducing PAX5-PML. Pro B cells derived from mouse fetal liver were transfected with PAX5-PML expression vector and transplanted into mice. All 8 transplanted mice died with pro B ALL from day 63 to 158. Leukemic cells could be serially transplanted and mice died more rapidly with repetition (Figure A). Among the target genes transcriptionally activated by PAX5, expressions of BLNK, Fcer2a, and CD72 were significantly repressed in leukemia cells but repression of CD19 and CD79a were mild, suggesting the importance of down regulation of these genes for differentiation block. We compared mRNA expression profile between leukemia cells and normal pro B cells and gene set enrichement analysis (GSEA) identified candidates for second hits for development of leukemia. We analyzed the mechanism of the selective repression of CD19, Fcer2a, and BLNK and the significance of the second hit candidates, using a cell line established from leukemia cells of the third transplanted mouse. The results will show the meeting.

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Figure 1

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