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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA082834-06
Application #
7055023
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (O1))
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
6
Fiscal Year
2006
Total Cost
$164,485
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Farina, Nicholas H; Zingiryan, Areg; Vrolijk, Michael A et al. (2018) Nanoparticle-based targeted cancer strategies for non-invasive prostate cancer intervention. J Cell Physiol 233:6408-6417
Tracy, Kirsten M; Tye, Coralee E; Page, Natalie A et al. (2018) Selective expression of long non-coding RNAs in a breast cancer cell progression model. J Cell Physiol 233:1291-1299
Hong, Deli; Fritz, Andrew J; Gordon, Jonathan A et al. (2018) RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol :
Ghule, Prachi N; Seward, David J; Fritz, Andrew J et al. (2018) Higher order genomic organization and regulatory compartmentalization for cell cycle control at the G1/S-phase transition. J Cell Physiol 233:6406-6413
Fritz, Andrew J; Ghule, Prachi N; Boyd, Joseph R et al. (2018) Intranuclear and higher-order chromatin organization of the major histone gene cluster in breast cancer. J Cell Physiol 233:1278-1290
Araya, H├ęctor F; Sepulveda, Hugo; Lizama, Carlos O et al. (2018) Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2. J Cell Biochem 119:8204-8219
Carver, Gary E; Locknar, Sarah A; Weaver, Donald L et al. (2018) Real-time detection of breast cancer at the cellular level. J Cell Physiol :
Tracy, Kirsten M; Tye, Coralee E; Ghule, Prachi N et al. (2018) Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer. Mol Cancer Res 16:587-598
Zaidi, Sayyed K; Fritz, Andrew J; Tracy, Kirsten M et al. (2018) Nuclear organization mediates cancer-compromised genetic and epigenetic control. Adv Biol Regul 69:1-10
Hong, Deli; Fritz, Andrew J; Finstad, Kristiaan H et al. (2018) Suppression of Breast Cancer Stem Cells and Tumor Growth by the RUNX1 Transcription Factor. Mol Cancer Res 16:1952-1964

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