2022 Pilot Awards and Fellowships.

Evans Pilot Awards

“Multi-Epitope Specific Cytotoxic CD4+ T Cells for Adoptive Immunotherapy of Myelodysplastic Syndrome” 
Lead Investigators: Pawel Muranski, MD and Amer Assal, MD 
Co-investigators: Azra Raza, MD, professor of medicine, director of the MDS clinical program, and co-director of the Edward P. Evans MDS Center; Markus Y. Mapara, MD, professor of medicine; Mithil K. Soni, PhD, associate research scientist at Columbia Center for Translational Immunology 

Stem cell transplant provides a chance to cure MDS, but due to the treatment’s toxicity, only younger and healthier patients are eligible. For all others, therapeutic options are limited to hypomethylating agents that only offer modest survival benefits. The team plans to apply novel techniques, developed by Dr. Muranski, in the production of tumor-specific T cells directed against tumor-associated antigens that are known to be expressed by neoplastic cells in MDS. Dr. Muranski and his colleagues believe this project is of high relevance to MDS as it lays the groundwork for a novel therapeutic approach to treat this often-fatal illness, particularly in patients who are transplant ineligible.

“Systematic Protein Structure Characterization of Mis-spliced Transcripts in Myelodysplastic Syndromes” 
Lead Investigator: Raul Rabadan, PhD 
Co-Investigator: James Manley, PhD, professor of life sciences

RNA splicing is a process that transforms a precursor messenger RNA (mRNA) into a mature one. Dysfunction of the splicing machinery is a key contributor to many human diseases and disorders, including MDS. Despite interest in dissecting the pathogenic consequences of mis-spliced versions of mRNA in MDS, little is known about the structural and functional changes in protein products. The project combines the unique expertise of two labs — computational cancer genomics (Dr. Rabadan) and RNA splicing (Dr. Manley) — to examine the structures of proteins arising from mis-splicing to learn about their functional consequences and explore potential therapeutic targets for MDS.

Evans Fellowships

“Functional-Dysfunctional Mitochondrial Exchange Between Mesenchymal and Dysplastic Stem Cells Drives MDS to AML Transformation” 
Lead Investigator: Rossella Labella, PhD

In the last decades, significant efforts have been made to understand the development of MDS and its transformation to AML. Uncovering the mechanisms behind disease transformation is crucial to developing the means to prevent it. Dr. Labella previously found that AML cells transfer dysfunctional mitochondria to heathy mesenchymal stem cells (MSCs), while healthy MCSs provide their functional mitochondria to AML cells. As a result, mitochondrial function of AML cells improves. Dr. Labella aims to perform additional experiments to fully delineate the role of mitochondrial transfer in MDS to AML transformation and to identify the molecular mediators in this process.

“Understanding the Role of Epitranscriptional Regulation in MDS Pathogenesis” 
Lead Investigator: Junsong Zhou, PhD

MDS originates from abnormal hematopoietic stem cells (HSCs) with accumulating genetic and epigenetic mutations. Understanding the novel molecular and cellular mechanisms underlying MDS pathogenesis is fundamental for devising novel therapies. Dr. Zhou aims to investigate parts of the epitranscriptome, which includes all the biochemical modifications of the RNA within a cell, for possible answers. Previously, he found that deletion of Mettl3, a type of modification enzyme, leads to HSC differentiation defects and other features of MDS such as hemorrhagic complications, due to thrombocytopenia (low platelet count) and platelet dysfunction. His next set of experiments will uncover a previously unappreciated contribution by epitranscriptional regulation to MDS and may lead to novel therapeutic targets.