Edward P. Evans Center for Myelodysplastic Syndromes Announces 2023 Pilot Awards and Fellowships
Four teams of researchers at Columbia University have been awarded 2023 Edward P. Evans Center for Myelodysplastic Syndromes (MDS) Pilot Awards and Fellowships. Pilot award winning projects will each receive a one-year $100,000 grant from the Evans Center while fellows will be provided with $60,000/year for two years to support their research.
MDS refers to a group of rare precancerous disorders that occur when blood forming cells in a patient's bone marrow begin to act abnormally. More than 40,000 individuals are diagnosed with MDS each year, and roughly one-third of those patients will develop acute myeloid leukemia (AML), an aggressive and difficult-to-treat form of blood cancer. In 2021, with the support of the Edward P. Evans Foundation, the Herbert Irving Comprehensive Cancer Center established the Evans Center with the goal of advancing novel treatments to prevent MDS and its progression to AML.
About the Winning Projects
“Modeling Human Clonal Hematopoiesis of Indeterminate Potential (CHIP), MDS, and AML Using in Vitro Hematopoiesis from Gene-Edited Induced Pluripotent Stem Cells”
Lead Investigator: Yong-Oon Ahn, PhD, associate research scientist
In elderly individuals, a process known as clonal hematopoiesis of indeterminate potential (CHIP) occurs, in which hematopoietic stem cells (HSCs) multiply, creating clones with mutations. These mutations can lead to MDS, and even further mutations can progress the condition to AML. This study utilizes induced pluripotent stem cells (iPSCs), which are cells derived from healthy donors or patients and used to study cancer and other diseases. Using iPSCs, Dr. Ahn plans to model the clonal evolution that occurs during CHIP and its progression to MDS and AML. The iPSCs used will be genetically modified and then differentiated into HSCs, myeloid, and NK cells, and single-cell analysis will be conducted to understand each cells’ growth and transformation to explore potential treatments for MDS/AML.
“Investigate the Impact of Genotoxic Therapies on rDNA Instability at the Single Cell Level and Its Role in Therapy-Induced MDS/AML”
Lead Investigator: Xiaolu Zhu, PhD, post-doctoral research scientist
Co-Investigator: Shan Zha, MD, PhD, professor of pathology and cell biology, Institute for Cancer Genetics; professor of microbiology and immunology, Herbert Irving Comprehensive Cancer Center; James A. Wolff professor of pediatrics, Department of Pediatrics
Therapy-related MDS (t-MDS) is a late and aggressive complication of anti-cancer treatments with a dismal prognosis. t-MDS is caused by DNA damage or selection that occurs as a side-effect of chemotherapy. Although there is a general connection between accumulative DNA damage and the development of MDS, the exact type of damage and genomic elements involved in MDS's development remain unknown. Dr. Zhu and colleagues have recently developed several new tools to assess genomic instability in ribosomal DNA (rDNA). During their fellowship, Dr. Zhu will address why specific genotoxic agents, but not others, pose a high risk for t-MDS and the repair pathways, and investigate the mechanism that suppresses rDNA instability.
Winning Pilot Awards
“Predicting AML by Means of m6A and YTHDF Proteins Activity”
Lead Investigator: Sara Zaccara, PhD, assistant professor, Department of Systems Biology
For decades, it was believed that information in messenger RNA (mRNA) was confined to its nucleotide sequence. However, new methods to study mRNA have shown it contains additional information in the form of chemical modifications. The most common of these modifications is called N6-methyladenosine (m6A) and Dr. Zaccara’s past research has shown that AML depends on m6A in order to develop. Currently it is unknown whether the events that cause m6A and other chemical modifications could be used as a diagnostic tool for detecting the earliest stages of AML. Dr. Zaccara’s pilot project hopes to identify whether m6A could be considered a biomarker of MDS progression to AML and understand mechanisms underlying m6A regulation during that progression. Overall, these studies have the potential to fundamentally change the current view of how m6A functions during AML progression and provide alternative therapeutic avenues for AML treatment.
“Nucleolar Dysfunction as a Therapeutic Liability in Cohesin Mutant MDS”
Lead Investigator: Aaron Viny, MD, assistant professor of medicine, Department of Medicine and Columbia Stem Cell Initiative
Co-Investigator: Hans Scnoek Willem, MD, PhD, Byron M. Thomason professor of medicine (in Microbiology and Immunology)
The genes that control gene expression are frequently mutated in blood cancers. STAG2 is a gene that helps control DNA organization within the nucleus and is recurrently mutated in MDS. Dr. Viny's lab has observed that mutations cause fragmentation in the nucleus in MDS patient bone marrow cells and genetically engineered mouse models. This project hypothesizes that STAG2 mutations induce stress in the nucleus as a result of the loss of rDNA loop structure. In this proposal, Dr. Viny and collaborators will test the hypothesis that nucleolar stress in mutant AML represents a mutation-specific therapeutic liability and investigate the role of nucleolar dysfunction.