NCN OPUS 21 - "Epigenetic Reprograming and All-trans-Retinoic Acid in Therapy of Myelodysplastic Syndromes"

01.08.22

On August 1, 2022. the OPUS 21 project "Epigenetic Reprograming and All-trans-Retinoic Acid in Therapy of
Myelodysplastic Syndromes " has started at the Institute of Animal Genetics and Biotechnology PAS. The project manager is Dr. Artur Zelent.

Our long-term goal is to design new therapeutic strategies for patients with myelodysplastic syndromes (MDS), which are fatal diseases with no curative therapy outside the context of stem cell transplantation. MDS comprise a heterogeneous group of clonal hematopoietic stem cell malignancies with significant morbidity and high mortality. The lack of effective MDS therapies contributes to rising mortality, mostly due to opportunistic infections (70%) and transformation to acute myeloid leukemia (AML) (30). About 80 percent cases are diagnosed in a group of people over 60 years of age (more often in men). The annual number of cases in Poland is around 2000. Deregulated epigenetics has been functionally linked to MDS.Following from our experience in AML, and recent preliminary data with MDS patients, it is our view that combined therapy with all-trans-retinoic acid and tranylcypromine (ATRA/TCP) will overcome two key treatment resistance mechanisms in MDS: epigenetic deregulation and clonal heterogeneity. Our central hypothesis is that in MDS, loss of ASXL1 expression sensitizes MDS cells to ATRA and that inhibition of LSD1 will restore the therapeutic effects of this agent via epigenetic reprograming, thereby also reducing cellular heterogeneity and limiting the emergence of resistant sub-clones. To test our central hypothesis, we propose the following specific aims: 1) Determine whether the loss of ASXL1 expression affects activity of RARs and LSD1, and response of MDS to ATRA/TCP; 2) Demonstrate the effect of ATRA/TCP treatment on genome wide H3K4me2 and gene expression patterns; and 3) Determine cellular heterogeneity using single cell gene expression analysis before, during and after treatment, and correlate these data with disease outcomes. Based on our published and preliminary data, the studies proposed in this project will test the combination of TCP with ATRA for MDS patients to extend the success of ATRA into all MDS subtypes.

Project value: 2 657 160 PLN. The project is financed by the National Science Center

Project start date: August 1, 2022

Planned completion date of the project: July 31, 2025