Haploinsufficiency of transcription factors EBF1 and PAX5 in pro-b cell leukemia

Early B-cell factor1 (EBF1) and PAX5 are transcription factors that are both essential for normal B lymphopoiesis and the maintenance of B cell identity. Hemizygote deletions of EBF1 or PAX5 are often found in human B cell acute lymphoblastic leukemia (B-ALL), however the role of these transcription factors in these malignancies is not fully understood. To gain insight into the role of EBF1 and PAX5 in B-ALL, we analyzed Ebf1(+/-)Pax5(+/-) double heterozygote (dHet) mice, which develop B-ALL. By microarray analysis and in vivo blocking experiments using anti-IL-7 receptor antibody, we found that the IL-7/STAT5 pathway is essential for the survival and proliferation of Ebf1(+/-)Pax5(+/-) dHet leukemic cells. Furthermore, to understand the molecular mechanism, ChIP-seq analyses to detect chromatin binding of EBF1 and Pax5 were conducted. This analysis indicated that the occupancy of EBF1 and/or Pax5 is lost at many binding sites in leukemic cells. However, we also observed the gain of occupancy at specific sites in leukemic cells. Together, our results provide insight into mechanisms that result in the development of leukemia in cells with reduced expression of EBF1 and Pax5.