Project A2 (End): Dissecting hematopoietic defects in Mixed-Lineage-Leukemia 5 (MLL5) in the DNA damage response and its potential effects on leukemogenesis
MLL5 is located in a genomic region (chr.7q22) recurrently deleted in leukemic cells from MDS- and AML-patients. As we have shown previously, Mll5-deficient mice exhibit multiple defects in the hematopoietic stem and progenitor cell (HSPC) compartment, consistent with a proposed role of Mll5 in leu-kemogenesis, although no overt leukemia has been observed as yet. During the first funding period, we un-covered that loss of Mll5 results in accrued DNA damage and elevated levels of reactive oxygen species (ROS), which turned out to be the underlying cause of most hematopoietic abnormalities in Mll5-/- mice. We propose three major lines of investigation: First, to directly evaluate the effects of ROS on AML malignancy, we wish to xenograft primary human AML cells with -7/7q- into immune-deficient NSG mice, which then will or will not be treated with an effective anti-oxidant. Second, we propose to conduct experiments to identify genetic and environmental events potentially cooperating with Mll5-deficiency to trigger overt leukemia. Finally, using a set of molecular tools generated during the first funding period, we wish to dissect Mll5 function in DNA repair and ROS induction at the molecular level.
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