CLONING AND DEVELOPMENTAL EXPRESSION OF THE MURINE HOMOLOG OF THE ACUTE-LEUKEMIA PROTOONCOGENE AF4

AF4 is the 4q21 gene involved in the acute lymphoblastic leukemia asso ciated t(4;11)(q21;q23) where it forms a fusion gene with MLL, In orde r to gain insight into AF4's role in leukemogenesis we have studied it s functional domains and expression pattern during murine development, We have cloned the murine homolog, Af4. We have demonstrated that 5' half of Af4 encodes a region with transcriptional transactivation acti vity which is disrupted by the t(4;11) in human leukemias, We have als o localized the murine AF4 protein to the nucleus supporting a role fo r AF4 in transcription, The developmental expression pattern of Af4 wa s determined in situ hybridization and suggests Af4 plays an important role in the development of the hematopoietic, cardiovascular, skeleta l and central nervous systems, A repeating pattern of Af4 expression i n development is downregulation with differentiation of a tissue, Amon g the cell types where this pattern of down-regulation is noted are B- lymphocytes. These findings raise the possibility that the disruption of normal AF4 function by the translocation may contribute to leukemog enesis.