Temporal Changes in FLT3-ITD Regulation of Stem Cell Self-Renewal and Leukemogenesis
Abstract
My goal is to understand how mechanisms that regulate normal hematopoietic development can also influence the mutation spectra of pediatric and adult acute myeloid leukemia (AML). Genetic differences between pediatric and adult AML may underlie differences in outcomes and necessitate different treatment strategies, yet we have few insights into why these differences occur. To address this problem, we are testing whether one mutation, FLT3-ITD, differentially regulates fetal and adult progenitors. FLT3-ITD mutations are more common in adult AML than in childhood AML, and our studies to date have shown that it has age-specific phenotypes. In adult mice, FLT3-ITD depleted the hematopoietic stem cell (HSC) pool and expanded myeloid progenitor populations. These phenotypes were not evident in fetal mice, even in the presence of a collaborating Runx1 mutation. To understand why fetal and adult progenitors responded differently to FLT3-ITD, we characterized signal transduction (e.g. STAT5 and MAPK pathways) in fetal, neonatal and adult progenitors. STAT5 was activated by FLT3-ITD at all stages of development, but MAPK was activated only in post-natal progenitors. Furthermore, STAT5 target gene regulation changed through the course of development. We are now testing whether reactivation of fetal gene products can suppress leukemogenesis. Reprogramming therapies may offer a novel approach for treating AML.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2015
- Accession Number
- AD1001728
Entities
People
- Jeffrey A Magee
Organizations
- University of Washington