Identifying Factors Regulating CD19 Alternative Splicing in Pediatric B-ALL

Background

B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common childhood cancers. Recent medical developments resulted in the creation of highly effective immunotherapies that guide the patient's own immune system to fight the leukemia with high success rates among patients with chemotherapy-resistant B-ALL. One such immunotherapy is CART-19, which targets CD19, a protein present on the surface of B-ALL cells. CART-19 has been very successful, with nearly 9 out of 10 patients cured of B-ALL. Unfortunately, there have been children who have relapsed following treatment and have gained a resistance to CART-19.

Recent research suggests one of the mechanisms of resistance to CART-19 is through a process called alternative splicing, which results in an altered shape of the CD19 protein. During the process of protein synthesis, splicing assembles together discrete building blocks called exons to form a complete protein. In alternative splicing, certain exons are skipped and not included in the final product, resulting in a shortened protein often with a different shape. The consequence of this in the B-ALL patients is that immunotherapies like CART-19 cannot recognize CD19 when exons are skipped. One of these cases of exon skipping in B-ALL patients involves the skipping of exons 5 and 6 in the CD19 protein.

Project Goal

The goal of this project is to identify factors involved in the regulation of alternative splicing of exons 5 and 6 of the protein CD19 to gain a better understanding of why the relapsed patients developed resistance to the CART-19 immunotherapy.