Disrupted differentiation and oncogenic transformation of lymphoid progenitors in E2A-HLF transgenic mice

The hepatic leukemia factor (HLF) gene codes for a basic region-leucine zip per (bZIP) protein that is disrupted by chromosomal translocations in a sub set of pediatric acute lymphoblastic leukemias. HLF undergoes fusions with the E2A gene, resulting in chimeric E2a-Hlf proteins containing the E2a tra nsactivation domains and the Hlf bZIP DNA binding and dimerization motifs. To investigate the in vivo role of this chimeric bZIP protein in oncogenic transformation, its expression was directed to the lymphoid compartments of transgenic mice. Within the thymus, E2a-Hlf induced profound hypoplasia, p remature involution, and progressive accumulation of a T-lineage precursor population arrested at an early stage of maturation. In the spleen, mature T cells were present but in reduced numbers, and they lacked expression of the transgene, suggesting further that E2a-Hlf expression was incompatible with T cell differentiation. In contrast, mature splenic B cells expressed E2a-Hlf but at lower levels and without apparent adverse or beneficial effe cts on their survival. Approximately 60% of E2A-HLF mice developed lymphoid malignancies with a mean latency of 10 months. Tumors were monoclonal, con sistent with a requirement for secondary genetic events, acid displayed phe notypes of either mid-thymocytes or, rarely, B-cell progenitors. We conclud e that E2a-Hlf disrupts the differentiation of T-lymphoid progenitors in vi vo, leading to profound postnatal thymic depletion and rendering B- and T-c ell progenitors susceptible to malignant transformation.