MYB GENE AND HUMAN HEMATOPOIESIS

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

Description (taken directly from the application): Disrupting the expression of hematologically relevant protooncogenes with antisense oligodeoxynucleotides (ODN) can yield functionally informative data with important translational significance. Based on work of this type, we have begun clinical trials with an antisense molecule targeted to the myb gene. Though our trials are still in Phase I, it is clear to us that while myb is a rational target, it is still less than perfect for treatment of hematopoietic malignancies because it is expressed by both normal and malignant cells. We propose to address this problem by developing a more in-depth knowledge of myb biology in normal and malignant hematopoietic stem/progenitor cells. We have developed three specific aims which support our goal: 1. Identify myb-regulated genes and the mechanism whereby these targets are transactivated: We intend to identify physiologically significant targets of the myb transcription factor using differential screening, expression assays, deletion and mutation assays, gel shifting/foot printing, and antisense disruption. New, potentially tumor specific targets for antisense mediated inhibition of tumor growth may be identified in this manner; 2. Further define how myb functions by identifying interacting proteins: The activity of many transcription factors is regulated by interaction with other nuclear proteins. MYC-MAD-MAX, MYO-D-ID, p53-mdm2 are well known examples. Because the myb protein has domains which are permissive of such interactions, we hypothesize that myb function is also regulated by interaction with as yet unidentified binding partners. Using standard screening approaches, and a novel method based on flow cytometric screening for protein expression, we will identify physiologically relevant myb binding partners. Novel therapeutic targets may also be discerned by this line of investigation; 3. Determine the effect of integrin-mediated lymphocyte adherence on c-myb expression: Integrin-mediated cell adhesion, through a process known as "outside-in" signaling, initiates intracellular signal transduction pathways that can modulate gene expression. Based on the important role played by myb in hematopoietic cell development, we hypothesize that integrin mediated interaction of hematopoietic cells with components of the extracellular matrix will modulate myb expression and the consequent downstream events which regulate hematopoietic development.