The AML1/CBFbeta transcription factor complex is one of the most frequent targets of genetic alterations in human acute leukemia, being targeted in up to one-third of acute myeloid and lymphoblastic leukemia by either chromosomal induced rearrangements, or point mutation. Prior work from my laboratory has demonstrated that AMNL1 normally functions as a master regulatory transcriptional switch that is essential for the formation of the definitive hematopoietic systems. In our preliminary data, we now extend this observation to show that AML1/CBFbeta establishes, in a dose-dependent manner, a transcriptional cascade that is required for the formation of definitive hematopoietic stem cells (HSCs) in the aorta-gonad mesonephros region (AGM) of the developing embryo. Moreover, subtle alterations in the level of AML1/CBFbeta induces dramatic changes in the temporal and spatial generation of HSCs, shifting them from their normal position in the AGM to the yolk sac. The initiation of leukemia by chromosomal rearrangement-induced-induced alteration in ABL1/CBFbeta appears to result at least in part, from a partial dominant negative inhibition of normal AML1/CBFbeta, leading to alterations in the self-renewal and maturation of HSCs. Importantly, however, our preliminary data clearly demonstrates that AML1-ETO alone is insufficient to induce leukemia, but rather must cooperate with secondary genetic alterations to transform HSC. Based on these observations, our working hypothesis is that a certain threshold level of AML1/CBFbeta is required for the function of HSC. Genetic changes that decrease the activity of the complex below this level directly alter HSC growth, leading to a pool of """"""""pre-leukemic) cells that must acquire secondary mutations before they can generate a full leukemic phenotype. To directly address this hypothesis, experiments are proposed in Specific Aim 1 that will utilize a conditional AML1-ETO knock in-mouse that was recently generated in my laboratory to define the spectrum of secondary mutations able to cooperate with AML1-ETO to induce leukemia.
In Specific Aim 2, we will extend these studies to determine how AML1 mutations identified in familial and sporadic cases of AML predispose to leukemia through the generation of mice containing these mutations in their germline. Together these studies should provide critical insights into the molecular pathology of the core-binding factor leukemia. Moreover, the murine models developed through these efforts should prove to be valuable reagents through which to assess the potential therapeutic use of drugs targeted toward either AML1-ETO or its bound nuclear co-repressors.
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