Rosannah Cameron, PhD | Aplastic Anemia and MDS International Foundation

Rosannah Cameron, PhD

The role of spliceosome in regulating DNA methylation in myelodysplastic syndrome
Original Research Center: 
Albert Einstein College of Medicine
Pubmed Author Name: 
Cameron R
Current Position/Title: 
Research Fellow, Department of Developmental & Molecular Biology

We do not yet fully understand the process of disease progression in MDS. We know certain genes are involved because mutations in those genes have been found in MDS patients. We need to understand which genes are important early in the disease and which ones act later. Our goal is to identify the genes that act early in MDS, so that ultimately, our research will lead to new treatment options that are more specific and effective.

First Year Report: 

The goal of our research is to gain a better understanding of disease progression in myelodysplastic syndrome (MDS) so more effective therapies can be identified. We are investigating the role of genes that are mutated early in disease progression. These early mutations are thought to have a role in driving the disease and could pre-dispose the cell to further mutations resulting in more severe disease. We are studying mutations in two groups of genes that are commonly mutated in MDS, regulators of epigenetic modifications and regulators of splicing. Both of these processes are tightly regulated in normal cells and alterations to them could affect many different genes. We want to understand how these two processes interact in MDS, and how they could trigger downstream mutations. Our research involves using zebrafish with a mutation in a key splicing factor, sf3b1, to look at what happens to epigenetic modifications when you lack Sf3b1. Zebrafish are useful for this type of study as they have a short generation time, their embryos are transparent and easy to manipulate. Additionally zebrafish have equivalents of almost all human genes.

We have found that mutations in sf3b1 lead to a decrease in the levels a key epigenetic gene, tet2. The tet2 gene produces an enzyme that modifies DNA by converting a methyl (5mC) residue to a hydroxymethyl residue (5hmC). We found a reduction in the overall levels of 5hmC in our sf3b1 mutant zebrafish. The levels of 5hmC are known to be altered in MDS and numerous other cancers. Our data provides evidence of a link between splicing and epigenetic modifiers. We hope to further our understanding of how these processes interact and determine how this interaction could affect other genes in the context of MDS. This research will provide valuable insight into the processes that are altered early in MDS and will facilitate the development of more effective therapies.

Final Report: 

Myelodysplastic syndromes are a group of diseases that occur when blood cells acquire multiple mutations or genetic changes that alter cellular function and behavior. These mutations can occur as a normal byproduct of aging or can result from exposure to certain mutagenic agents. All mature blood cells are produced by hematopoietic stemcells (HSCs) via the formation of intermediate cells known as progenitors that will eventually give rise to all mature blood cell lineages. When mutations occur early in this process numerous downstream cells inherit these mutations and can then acquire further mutations resulting in a loss of the ability to make functional mature blood populations. The loss of normal functions in these cells is reflected in the low blood cell counts observed in MDS patients. Current therapies are often ineffective at removing mutated HSCs and early progenitors that can restart the MDS process resulting in relapse.

The goal of our research is to understand the earliest mutations and changes that occur in HSCs and their progenitors, so we can develop more effective therapies that efficiently target the majority of mutated cells. We are using zebrafish to study how mutations in two groups of factors thought to be drivers of disease (splicing factors and epigenetic modifiers) interact in MDS and how they could pre-dispose cells to further mutations. Our zebrafish have a mutation in a key splicing factor, sf3b1 (splicing factor 3b, subunit 1), which is one of the most commonly mutated genes found in MDS patient blood cells. These mutants have defects in early hematopoiesis, reinforcing the importance of splicing factors in blood cell development. Zebrafish are useful for this type of study due to their short generation time, ease of manipulation and they also have equivalents of almost all human genes.

In addition to splicing factors, we are also interested in epigenetic modifiers, specifically TET2, the most commonly mutated epigenetic modifier in MDS. TET2 encodes an enzyme that is important in DNA methylation, which is part of a global mechanism of regulating when genes are turned on or off. We found reduced levels of the tet2 gene in sf3b1 mutant zebrafish. We also found that tet2 and sf3b1 interact during early blood development in zebrafish. Additionally, we used a powerful technique to identify all the genes that were mis-regulated in sf3b1 mutants. From this analysis, we identified a number of epigenetic modifiers that are mis-regulated in response to loss of sf3b1 and we will be investigating how these genes alter the behavior and function of blood cells. Finally, we are performing a small molecule screen to look for compounds that correct the blood defect we see in sf3b1 mutants. This screen will be valuable in finding drugs that could represent novel therapeutic agents for MDS treatment.

Due to the generous support from the Aplastic Anemia & MDS International Foundation, we took a valuable step forward in understanding how early mutations contribute to the disease process in MDS. The data generated by this work will continue to be utilized to better understand how mutations in splicing and epigenetic genes contribute to blood development and how their mis-regulation can result in MDS.

Current Institution: 
Albert Einstein College of Medicine