Myelodysplastic syndrome (MDS) is a condition where blood cells do not develop normally, and our understanding of this disease has improved markedly over the past decades. One important discovery was that specific genes are mutated sequentially, which sheds light on how diseased cells arise from healthy blood cells. The Majeti lab has contributed to this knowledge by pinpointing early mutations that occur in blood stem cells called pre-malignant stem cells. Early mutations often occur in a gene called ASXL1. About one in five MDS patients have mutations in the ASXL1 gene, which is thought to regulate the activation of other genes. Patients with ASXL1 mutations face high-risk disease and poor outcomes, including a higher chance of developing acute myeloid leukemia. Research in the field has mapped the journey from healthy blood cells to MDS. The earliest stage begins when blood stem cells gain initiating mutations in genes like ASXL1, followed by later stages where additional mutations occur in other genes, eventually transforming into disease.

Our knowledge about ASXL1 mutations is still limited, mainly due to the lack of model systems that mimic MDS. Currently, treatment approaches for patients with ASXL1 mutations are not available. To address this gap, recent efforts in our lab have made progress in understanding how ASXL1 mutations lead to blood cell abnormalities. First, we have developed a laboratory model that simulates disease conditions by introducing ASXL1 mutations into human blood stem cells. This model shows similar characteristics to MDS, including increased stem cell traits and a tendency to progress toward advanced stages of disease. Second, we recently created a gene editing technique that allows us to correct mutations and restore a gene to its normal state. Third, upon inspecting a population of blood cells with abnormal stem cell properties, we found that ASXL1 mutations lead to increased levels of a protein called CD24. This particular protein can act as a “don’t eat me” signal to the immune system that works, in part, to phagocytose abnormal cells for defense. However, researchers in other fields have found that abnormal cells can stealthily exploit CD24 to trick the immune system and escape destruction. Taken together, our research goals are:

1. 1)  Determine whether ASXL1 mutations are crucial for initiating MDS and its progression, and/or if these mutations are responsible for activating other genes only in the early stages of disease.
2. 2)  Identify the exact cell type(s) that expresses CD24 and determine whether targeting the CD24 “don’t eat me” signal leads to the phagocytosis of diseased cells and elimination of the disease.

By achieving these goals, our research will uncover how ASXL1 mutations contribute to different stages of MDS and increase our understanding of how ASXL1 mutations cause blood cell abnormalities. Additionally, this work will explore new treatment options for patients with these mutations and may indicate the potential application of CD24-targeting therapies for improving MDS outcomes.