MLL-FUSIONS AND COOPERATING MUTATIONS IN ACUTE LEUKEMIA

Loyola University Chicago, Maywood IL

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Abstract

PROV1IJED. The MIL gene at chromosome band 1 Iq23 is rearranged frequently in de novo and in therapy-related leukemia. The consequence of these translocations is the formation of a chimeric protein that consists of N-terminal sequences from MLL fused in frame to C-terminal sequences of its partner genes. Previous!)', we cloned the ELL gene involved in the (11;19)(q23;pl3.1) translocation, one of the most common of 1 Iq23 aberrations. To characterize these leukemias in detail, we used two alternative strategies to develop mouse models of MLL-ELL leukemia. Using retroviral infection of bone marrow followed by transplantation, recipient mice all develop acute leukemia in 5-6 months. In contrast, in a knock-in model of MI1-ELL generated by gene targeting, chimeric and heterozygous mice do not develop leukemia and exhibit no apparent hematopoietic phenotype, indicating that expression of the Mll-ELL fusion gene is insufficient by itself for the development of acute leukemia. However, treatment of the knock-in mice with ENU induces acute leukemia in 90% of mice that recapitulates the phenotype observed in the retrovira! transplant model and human acute leukemias in patients with (11;19)(q23;pl 3.1) translocations. Recent analyses of blood samples obtained at birth from childhood leukemia patients have revealedthat secondary genetic events are also required in the development of human leukemias. Using the MLL-ELL mouse leukemia models, we propose to use insertional mutagenesis identify the cooperating mutations that are required for the development of MLL-associated leukemia. To determine the critical changes in gene expression that result from the expression of MLL fusion genes, we plan to use microarrays to analyze (low sorted granulocyte/monocyte progenitor cells and myelomonocytic cells obtained from the Mil-Ell knock-in mice before and after treatment with ENU and from mice transplantedwith hematopoietic cell transduced with MLL-ELL. These studies will provide critical reagents for the characterization of 1 Iq23 leukemias, the pathways that cooperate in the development of leukemia, and the development of novel treatment strategies for this common subtype of leukemia.