New Discoveries in B-ALL Research Highlight PTBP1's Importance in CD19 Expression Regulation

The article discusses how relapses occur in patients with B-ALL despite improvements in CART-19 immunotherapy. The loss of the targeted epitope is often responsible for this relapse. Mutations and aberrant splicing events can cause the absence of surface antigen, but the early molecular determinants of therapy resistance and the time point when first signs of epitope loss appear are unknown. Through deep sequencing of the CD19 locus, the article identifies a blast-specific 2-nucleotide deletion in intron 2 that exists in 35% of B-ALL samples at initial diagnosis. This deletion overlaps with the binding site of RNA binding proteins, affecting CD19 splicing. The downregulation of PTBP1 reduces CD19 protein by increasing intron 2 retention. Isoform analysis in patient samples reveals that blasts at diagnosis express increased amounts of CD19 intron 2 retention compared to normal B cells. The article suggests that loss of RNA binding protein functionality may harbor the potential for the accumulation of therapy-resistant CD19 isoforms.