Harnessing METTL3 inhibition in acute megakaryoblastic leukemia driven by the t(1;22) fusion involving a member of the m6A writer complex
Manyi Wei
PhDYale
Project Term: July 1, 2024 - June 30, 2026
I want to understand how the t(1;22) translocation that involves a member of the m6A writer complex drives acute megakaryoblastic leukemia (AMKL). To identify culprit genes and pathways I will use multi-omics, including RNA, eCLIP, and TimeLapse Seq and proteomics. I will dissect the RBM15-MKL specific effects of a novel METTL3 inhibitor in primary murine and human AMKL in vitro and in vivo. My ultimate goal is to cure this rare infant leukemia by harnessing METTL3 inhibition.
Acute myeloid leukemia (AML) is a type of blood cancer characterized by the uncontrolled proliferation of immature blood cells that accumulate in the bone marrow at the expense of healthy blood cells, including white and red blood cells, and platelets. Acute megakaryoblastic leukemia (AMKL) is a subtype of AML. Its pathogenic mechanism involves the fusion of two genes, RBM15 and MKL1, which are normally separated. This fusion results in an abnormal protein with a new function promoting leukemia. Progenitor cells carrying this fusion gene continue to proliferate without normal differentiation into functional platelets which are crucial for blood clotting, leading to rapid patient deterioration. Despite the severity of AMKL, there is limited knowledge about the molecule changes induced by this fusion gene and potential treatment strategies. In a collaboration with Dr. Diane Krause and her laboratory I explore the cellular alterations associated with the fusion of RBM15 and MKL1 genes in AMKL. My project specifically focuses on the abnormal role related to RBM15 in the fusion protein. RBM15, as in his name “RNA binding protein 15” is a vital protein that binds ribonucleic acids “RNA” that carry all the information from the genome to make all necessary proteins in the cell. In that function, RBM15 modifies RNA to fine tune its journey in the cell. One of the fine-tuning mechanisms is RNA methylation. In a wonderful collaboration with STORM Therapeutics I am testing a novel drug they developed to treat AMKL specifically addressing RNA methylation. Our preliminary experimental results showed that their novel drug can inhibit RBM15-MKL1 driven AMKL cell proliferation and induce differentiation and cell death, both in the cell culture dish and a live leukemia model. In my future research I want to better understand how inhibition of this RNA methylation specifically kills these leukemia cells. I will use very sophisticated techniques to look at how all RNAs are changed both by the fusion protein and then by inhibition of its methylating effect and how that affects the proteins in the cell. I will also further look at how we can make use of the immune reaction we have identified in our live leukemia model in response to this treatment. This finding builds on an effect we have previously found in the Halene Lab. My hope is that my findings will result in a way to better treat this leukemia in young children and to may be one day avoid toxic chemotherapy altogether.