Team #2: Molecular Pathways

Understanding the Molecular Pathways Involved in the Production of Normal Blood Cells

Overview

Researchers in Team 2 are performing work similar to those in Team 1, except they are identifying the molecular pathways involved in the production of healthy blood cells. A comparison of the newly-discovered normal and abnormal pathways will allow researchers to pinpoint the molecular interactions that go awry in t-AML and identify therapeutic targets.

The Project In Detail

The development of normal blood cells is known as hematopoiesis. This process involves the interaction of numerous transcription factors, which are proteins that bind to the regulatory regions of genes to activate or suppress their expression. These transcription factors determine the fate of hematopoietic stem cells (HSCs), which mature into red or white blood cells, or platelets. However, the regulation of this process is poorly understood because transcription factors interact and form very complex “gene regulatory networks”.

Researchers in Team 2 hypothesize that these “networks” governing normal blood cell production and the development of AML are both shared and unique. They are developing powerful experimental systems to analyze these gene regulatory networks. With a research technique known as chromatin immunoprecipitation-sequencing (ChIP-Seq), researchers use antibodies to isolate transcription factors of interest while they are directly bound to specific DNA sites, followed by determination of the nucleotide sequences of the captured DNA. These interactions occur at the estimated 200-5,000 regulatory sites of the key genes in the network. Based on these results, they can use computational modeling to predict the gene networks, and most importantly, the critical ‘nodal’ factors within the network, that regulate normal blood cell production. Perturbing these key factors will reveal the molecular circuitary that underpins normal hematopoiesis. Using this information, they can then identify dysregulated networks in leukemic stem cells and ultimately design more effective drugs against these specific genetic defects.

Milestones

How does this Work Relate to the Work of Other Research Teams?

Members in Team 2 are developing a global map of the gene networks that regulate the production of normal blood cells. In collaboration with Team 1, whose members are developing a genetic profile of t-AML, researchers can compare and contrast the normal regulatory processes with those that are dysregulated to identify new therapeutic targets. Team 2 will work closely with Team 4 to test these therapeutic targets using an animal model.

Project-Related Activities & Publications

A Recurrent Network Involving the Transcription Factors PU.1 and Gfi1 Orchestrates Innate and Adaptive Immune Cell Fates