PROJECT SUMMARY

Myelodysplastic syndromes (MDS) are blood diseases that occur when the blood-forming hematopoietic stem cells (HSCs) in the bone marrow become abnormal. This leads to reduced production of one or more types of blood cells. MDS is considered a type of cancer, and significantly impacts patient’s health and lifespan. Over 20,000 cases of MDS are diagnosed in the USA per year. There are only three approved treatments for MDS, but these existing therapies (which cost in excess of $120,000 per patient annually) do not cure the disease. Although new treatments for MDS patient are being developed, we propose here a very different approach – can we prevent “at-risk” people from developing MDS by eliminating mutant stem cells that would give rise to the disease?

HSCs live in the bone marrow and are responsible for life-long regeneration of the blood system. Through a variety of processes, HSCs acquire random genetic mutations as we age. Most mutations have no effects, but sometimes the mutations occur in critical genes which are required for the normal activity of the HSC. Such mutations then provide that cell with a growth advantage compared to other HSCs and the mutant cells overtake the bone marrow. This situation is called clonal hematopoiesis of indeterminate potential (CHIP) and is a common condition in the elderly population, occurring in about 10% of people over the age of 65. While CHIP itself is not a pathogenic condition, people with CHIP are predisposed to the development of blood disorders such as MDS. Furthermore, people with CHIP are at increased risk for early mortality due to adverse cardiovascular events. Understanding how these mutations in HSCs lead to CHIP is important for deciphering the genesis of MDS (and other human diseases), and for developing new methods of treatment and prevention.

Many mutations which provide HSCs with abnormal growth in CHIP are also driving forces for development of MDS. However, for this condition of CHIP to progress to MDS, the mutant HSCs must acquire additional mutations. But the long timescale required for mutant HSCs to acquire additional mutations in the correct order presents a unique opportunity for preventing these diseases. Due to technological advances in genome sequencing, we can now reliably identify the presence of CHIP mutations in the blood of otherwise healthy individuals. If interventions could be developed that eliminate mutant HSCs before they can acquire the appropriate co-operating mutations required for MDS, we could potentially prevent MDS developing in people with CHIP. Our recent lab research has identified a set of genes that appear to specifically support the growth of these mutant HSCs, but not normal stem cells. In this project we will now investigate if these genes regulate the clonal expansion of mutant HSCs in CHIP, to determine if targeting these factors can inhibit the development of MDS, and to understand the molecular pathways which these genes regulate in HSCs and MDS. The longterm goal of this work is to identify methods to specifically impede the propagation of these mutant HSCs, allowing the normal HSCs a chance to repopulate the bone marrow and reducing the lifetime risk of an individual with CHIP developing a blood cancer.