Mechanisms of Leukemogenic Transformation by MLL-CALM

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DESCRIPTION (provided by applicant): Chromosomal rearrangements involving the Mixed Lineage Leukemia (MLL) gene at chromosome 11q23 are frequently seen in leukemias. Although more than 40 translocation partner genes have been identified for MLL, the precise mechanisms by which MLL-fusion partner proteins lead to leukemia remain unclear. We recently identified a novel chromosome 11 inversion in an infant with acute myeloid leukemia (AML) that juxtaposed MLL to the Clathrin Assembly Lymphoid Myeloid Leukemia (CALM) gene at 11q14. CALM was first identified as a translocation partner for AF10 - itself an MLL partner - in acute leukemias and lymphomas. The CALM protein directly interacts with clathrin and membrane lipids, and plays a key role in endocytosis and intracellular vesicle trafficking. Recently, mutations in the murine calm gene have been shown to account for the phenotype of the fill mouse, which has significant abnormalities in hematopoiesis and iron metabolism. The involvement of CALM as a translocation partner for two distinct genes in hematopoietic malignancies, together with its involvement in normal hematopoiesis, suggests that perturbation of normal CALM function contributes to the development of leukemia. The overall objective of this proposal is to study the biology of the MLL-CALM fusion protein in leukemogenesis. We hypothesize that the MLL-CALM translocation contributes to the development of myeloid leukemia by perturbing the normal function of both CALM and MLL. To begin to understand mechanisms by which the MLL-CALM protein is involved in the pathogenesis of AML, our first aim is to determine whether MLL-CALM expression results in transformation in vitro and leukemia in vivo. We will use the murine hematopoietic progenitor transformation assay to rigorously demonstrate that MLL-CALM expression results in transformation in vitro, and establish in vivo murine models of MLL-CALM-dependent leukemia. In addition, to more faithfully mimic the MLL-CALM leukemia phenotype, we will prepare an mll-CALM transgenic mouse. Finally, we will examine leukemogenesis in the context of fit1 -derived hematopoietic precursors. Our second overall aim is to identify mechanisms involved in MLL-CALM-dependent transformation. In these studies, we will focus on the role of three specific mechanisms - dimerization, transcriptional regulation and endocytosis - in MLL-CALM- and CALM-AF10-dependent transformation. Insights gained regarding CALM function may be generalizable to the large number of leukemias and lymphomas with CALM-AF10 translocations, and, in a broader sense, will contribute to our understanding of normal CALM biology.