The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
Open accessAbstract
The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor–armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms. Significance: CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms. Cancer Discov; 5(12); 1282–95. ©2015 AACR. See related commentary by Jackson and Brentjens, p. 1238. This article is highlighted in the In This Issue feature, p. 1225
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Metadata
- Authors
- Sotillo, E., Barrett, D. M., Black, K. L., Bagashev, A., Oldridge, D., Wu, G., Sussman, R., Lanauze, C., Ruella, M., Gazzara, M. R., Martinez, N. M., Harrington, C. T., Chung, E. Y., Perazzelli, J., Hofmann, T. J., Maude, S. L., Raman, P., Barrera, A., Gill, S., Lacey, S. F., Melenhorst, J. J., Allman, D., Jacoby, E., Fry, T., Mackall, C., Barash, Y., Lynch, K. W., Maris, J. M., Grupp, S. A., & Thomas-Tikhonenko, A.
- Venue
- Cancer Discovery
- Published
- 2015-12-01
- Volume
- 5
- Issue
- 12
- Pages
- 1282-1295
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2179454156
- Cited by
- 1,254
- References
- 8
- FWCI
- 30.55
- Type
- journal article
- Language
- en
- Open access
- green
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- Sotillo, E., Barrett, D. M., Black, K. L., Bagashev, A., Oldridge, D., Wu, G., Sussman, R., Lanauze, C., Ruella, M., Gazzara, M. R., Martinez, N. M., Harrington, C. T., Chung, E. Y., Perazzelli, J., Hofmann, T. J., Maude, S. L., Raman, P., Barrera, A., Gill, S., . . . Thomas-Tikhonenko, A. (2015). Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-15-1020
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
