Project 1 focuses on the linkage of nuclear architecture with gene regulation. Nuclear morphology isdramatically altered during hematopoietic differentiation and is diagnostic for oncogenic transformationand tumor progression. The hypothesis is that cooperative interactions between AML (RUNX) proteinsand other gene regulatory factors at distinct subnuclear foci support myeloid-specific transcriptionalcontrol. One of the recent key findings of this program is that abrogation of AML1 subnuclear targetingcauses a myeloid cell maturation arrest. Furthermore, a subnuclear targeting defect in the t(8;21)AML1/ETO fusion protein that is directly linked to the etiology of Acute Myelogenous Leukemia wasestablished. This project therefore examines the (i) molecular mechanisms, (ii) gene regulatorypathways, (iii) physiological processes, and (iv) mitotic functions that are coupled to the subnucleartargeting dependent activity of AML1. We will characterize the molecular basis of subnuclear targetingduring myeloid differentiation and its deregulation during leukemogenesis (Specific Aim 1)(collaboration with Projects 2 and 4). We will identify AML1 mediated regulatory pathways that dependon fidelity of intranuclear trafficking in myeloid cells (Specific Aim 2) (collaboration with Project 2). Toestablish the physiological relevance of our findings, we will examine the consequences of abrogatingsubnuclear targeting on biological control and cancer in murine animal models in vivo (Specific Aim 3).We will characterize AML-dependent mitotic control of gene expression and deregulation in cancercells (Specific Aim 4) (collaboration with Projects 2, 3 and 4). These studies will provide a mechanisticunderstanding at multiple biochemical, cellular and physiological levels of signal integration at AMLrelated subnuclear microenvironments that dynamically assemble to support AML responsive generegulatory programs that are altered during the onset and. progression of Acute MyelogenousLeukemia.Lay Summary: The structure and shape of the cell nucleus, as well as the intranuclear organizationand assembly of the regulatory machinery for gene expression, is dramatically modified during theonset and progression of leukemias. The goal of our project is to characterize how regulatory proteinsfunction together at nuclear microenvironments to control gene expression and how this process isdisrupted in leukemia. Our findings will provide a platform for novel approaches to cancer diagnosisand therapies.
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