The 11q23 cytogenetic locus is involved in a wide range of acute leukemia associated translocations. Numerous partner chromosomes form translocations with this locus producing three clinicopathologic syndromes. These are an acute lymphoblastic leukemia with mixed lineage features, acute myeloid leukemia with monocytic differentiation, and secondary acute leukemia in patients who have been treated with topoiomserase II inhibitors. The 11q23 gene involved, first named MLL (Mixed Lineage Leukemia), is a putative zinc finger transcription factor. The two fundamental goals of this proposal are to understand how topoiomserase II inhibitors induce secondary leukemia and what role an MLL fusion partner, AF-4, plays in development. In order to begin to understand the mechanism by which topoisomerase II inhibitors produce 11q23 translocations we will clone and sequence a number of secondary leukemia breakpoints. Their location will then be compared to the location of in vivo mapped MLL topoisomerase II binding sites. AF-4 (ALL- 1 fused to 4) is the 4q21 gene involved in the Acute Mixed Lineage Leukemia associated t(4;11)(q21;q23). Like all other characterized MLL translocations, the t(4;11) produces a fusion transcript encoding a putative chimeric protein. Although AF-4 has features such as a putative nuclear targeting sequence, basic regions, and proline-rich region which suggest it is a transcription factor its biochemical function is unknown. AF-4 is expressed in a wide range of tissues at varying levels including primitive hematopoietic cell lines. AF-4's wide range of expression suggests it has a prominent role in development. In order to understand AF-4's role in development and in so doing shed light on how AF-4 derived sequences contribute to leukemogenesis this proposal describes an analysis of the role AF-4 plays in murine development. Its goals are to clone the murine AF-4 ((mAF-4) gene, use mAF-4 probes in in situ hybridization experiments through murine development, and use the AF-4 genomic clones for gene targeting experiments in embryonic stem (ES) cells which will lead to the creation of mice lacking a functional mAF-4 gene. These mice will offer definitive information on AF-4's role in development. The ES cells will also be used in the in vitro """"""""embryoid body"""""""" model of hematopoiesis. The completion of this work will provide the basis for two long term programs of research; one whose goal is to understand the mechanism by which secondary leukemia translocations occur and how to control that process and the other which will elucidate the fundamental biology of the AF-4 gene.
| Atlas, M; Head, D; Behm, F et al. (1998) Cloning and sequence analysis of four t(9;11) therapy-related leukemia breakpoints. Leukemia 12:1895-902 |
| Baskaran, K; Erfurth, F; Taborn, G et al. (1997) Cloning and developmental expression of the murine homolog of the acute leukemia proto-oncogene AF4. Oncogene 15:1967-78 |
