Every successful cancer therapy story has Exhibit B, comprised of patients who either did not respond to the initial treatment or acquired resistance after a seemingly curative intervention. The CD19-directed chimeric antigen receptorarmed T-cell therapy (commonly known as CART-19) is the case in point. Although it has revolutionized treatment for B-cell acute lymphoblastic leukemia (B-ALL) in children and adults and gained swift FDA approval,~ 30% of patients relapse after complete responses, most often via the loss of the cognate CD19 epitope [1]. Under selective pressure of CART-19 some of MLL-rearranged B-ALL have the propensity to trans-differentiate into myeloid lineages with concomitant loss of CD19 expression [reviewed in [2]]. Transport of CD19 to the plasma membrane is another potentially vulnerable process [3] requiring the dedicated CD81 chaperone; and dysregulation of this gene was reported to contribute to resistance to another CD19-targeted immunotherapeutic blinatumumab [4]. Still, focal alterations of the CD19 gene and its transcript appear to play central role in resistance [5]. In December 2015 our group published in Cancer Discovery the first report addressing the mechanism of resistance to CART-19, based on the analysis of the first 4 patients enrolled in the clinical trial at the Children’s Hospital of Philadelphia [6]. We performed whole exome and RNA sequencing and immunoblotting on relapsed leukemias lacking the CART-19 epitope on the cell surface. We observed that “genetic alterations… accounted for CD19 protein loss in some… but not in other… samples”. For example, in sample CHOP101R we discovered frameshift mutations in exons 2 and 4. However, both were subclonal and collectively accounted for no more than 50% of CD19 alleles, implying the existence of additional mechanisms of gene inactivation. Indeed, we discovered prominent splicing alterations involving increased skipping of exon 2 and exons 5–6 in relapsed leukemias; these preexisting isoforms were later reported by others as well [7]. Of note, exon 2 is absolutely essential for the integrity of the CART-19 epitope [3] and exons 5–6 encode the CD19 transmembrane domain needed for presentation on the cell surface. Thus, our paper was entitled “Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy”, stressing the importance of both DNA-and RNA-based mechanisms.