Identification and characterization of genetic factors affecting MLL/KMT2A fusion proteins stability in MLL/KMT2A rearranged leukemias
Christian Marinaccio
PhDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
MLL1/KMT2A rearranged leukemias are the most common blood cancer occurring in children characterized by dismal prognosis. Given the importance of fusion proteins in driving the disease, I will determine factors affecting the fusion protein stability through a CRISPR/Cas9 screening approach in an innovative model system where the MLL fusions are endogenously tagged with a fluorescent protein. This will facilitate development of molecular glue degraders specifically targeting the MLL fusions.
Every year, about 16000 children in the United States and 300000 children globally are diagnosed with cancer. Blood cancers, in particular leukemias, represent a substantial portion of these pediatric cancer cases accounting for more than 20% of all childhood cancers. The majority of leukemias in children are caused by chromosomal translocations involving a gene called KMT2A and one of over 100 translocation partner genes. In a translocation, a portion of the chromosome containing the KMT2A gene incorrectly reattaches to a portion of the chromosome containing the translocation partner, leading to the generation of fusion proteins. This alteration and the resulting fusion protein lead to transformation of blood cells and development of leukemia.
Current treatment options for KMT2A rearranged leukemias are limited to chemotherapy and blood stem cell transplant, which produce variable response rates and more than often are not curative and lead to relapse of the leukemia. This indicates there is a need for new treatment options for these pediatric patients.
The KMT2A fusion protein plays a central role in the development of these leukemias and this alteration alone is capable of transforming normal blood cells in leukemic cells. Since proteins are continuously produced and degraded in the cell, I propose to study the mechanisms by which the fusion protein turnover is regulated in the leukemic cell. To achieve this, I will use a model system in which I engineered cells to produce a version of the fusion protein tagged with a fluorescent protein. In this way, the cells harboring the fusion protein are marked and can be screened to identify genes involved in the regulation of the fusion proteins. Specifically, a class of proteins called E3 ligases are responsible of targeting proteins for degradation and finding the specific E3 ligase responsible for the degradation of the fusion proteins will open up avenues for development of molecules called molecular glues, which are able to recruit E3 ligases and accelerate degradation of target proteins. Development of these new agents will allow to target the key fusion proteins that maintain leukemia, thus providing a new treatment option for childhood leukemia patients.