The role of FOXM1 downregulation in the development of clonal dominance in del(5q) MDS

Zhijian Qian

PhD

University of Florida

Project Term: July 1, 2018 - June 30, 2023

Project Summary

Myelodysplastic syndrome (MDS) is a type of blood cancer that occurs when the blood-forming stem cells in the bone marrow are damaged, leading to low numbers of one or more types of blood cells. In MDS patients, damage to the blood-forming stem cells is often caused by genetic alterations due to mutagens or other effects caused by aging. Sometimes, these damaged stem cells can have some abnormalities in their chromosomes. One such abnormality involves the deletion of a large fragment of chromosome 5 called del(5q), which leads to improper regulation of important genes that are responsible for regulating the normal function of blood-forming stem cells. The abnormal stem cells often gain the growth advantage over normal stem cells and develop into the dominant population, which is a key event contributing to the initiation and early progression of MDS. The molecular mechanisms underlying the development of a dominant population of abnormal blood-forming stem cells remain elusive. Our long-term goal is to identify early treatments for MDS patients with del(5q) by targeting the key molecular regulators that are improperly regulated as a consequence of deletion of chromosome 5 and play a critical role in promoting the development of a dominant population of abnormal stem cells in MDS patients. In this study, we will first focus on elucidating how the FOXM1 gene that is required for maintenance of normal blood forming stem cells is deregulated in MDS patients with del(5q) and how deregulation of FOXM1 contributes to the development of a dominant population of abnormal stem cells in vivo. Since FOXM1 regulates the activity of certain other genes, we are investigating these other gene targets as well. We are further interested in what regulates the expression levels of FOXM1. We will next determine whether pharmacologic inhibition of this FOXM1 eliminates the abnormal stem cells using animal models and MDS patient samples. Furthermore, understanding how FOXM1 is regulated as well as which genes FOXM1 regulates may provide other molecules to therapeutically target. This research program will advance our knowledge and understanding of the molecular basis of MDS and provide a proof of concept that may lead to the identification of new effective therapeutic strategies for the treatment of early stages of del(5q) MDS patients by targeting the critical FOXM1 pathway.