Project 1 focuses on the linkage of nuclear architecture with gene regulation. Nuclear morphology is dramatically altered during hematopoietic differentiation and is diagnostic for oncogenic transformation and tumor progression. The hypothesis is that cooperative interactions between AML (RUNX) proteins and other gene regulatory factors at distinct subnuclear foci support myeloid-specific transcriptional control. One of the recent key findings of this program is that abrogation of AML1 subnuclear targeting causes 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 was established. This project therefore examines the (i) molecular mechanisms, (ii) gene regulatory pathways, (iii) physiological processes, and (iv) mitotic functions that are coupled to the subnuclear targeting dependent activity of AML1. We will characterize the molecular basis of subnuclear targeting during myeloid differentiation and its deregulation during leukemogenesis (Specific Aim 1) (collaboration with Projects 2 and 4). We will identify AML1 mediated regulatory pathways that depend on fidelity of intranuclear trafficking in myeloid cells (Specific Aim 2) (collaboration with Project 2). To establish the physiological relevance of our findings, we will examine the consequences of abrogating subnuclear 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 cancer cells (Specific Aim 4) (collaboration with Projects 2, 3 and 4). These studies will provide a mechanistic understanding at multiple biochemical, cellular and physiological levels of signal integration at AML related subnuclear microenvironments that dynamically assemble to support AML responsive gene regulatory programs that are altered during the onset and. progression of Acute Myelogenous Leukemia. Lay Summary: The structure and shape of the cell nucleus, as well as the intranuclear organization and assembly of the regulatory machinery for gene expression, is dramatically modified during the onset and progression of leukemias. The goal of our project is to characterize how regulatory proteins function together at nuclear microenvironments to control gene expression and how this process is disrupted in leukemia. Our findings will provide a platform for novel approaches to cancer diagnosis and therapies.
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