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| Status |
Public on May 22, 2024 |
| Title |
Mis-splicing derived neoantigens and cognate T cell receptors in splicing factor mutant leukemias |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic mutations in the splicing machinery. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-specific T cell receptors (TCR) from both healthy donors and patients with leukemia. While circulating neoantigen-specific CD8+ T cells were identified in patients with active disease, they were dysfunctional with reduced inflammatory response gene signatures. In contrast, donor CD8+ T cells with tumor-reactive TCRs were present following curative allogeneic hematopoietic cell transplant. T cells engineered with TCRs recognizing an SRSF2 mutant-induced neoantigen in CLK3 resulted in specific recognition and cytotoxicity of SRSF2 mutant leukemia. These data identify RNA mis-splicing derived neoantigens and neoantigen-specific TCRs across patients and provide proof-of-concept to genetically redirect T cells to public mis-splicing derived neoantigens in myeloid leukemias.
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| Overall design |
We isolated bulk T cells from patient PBMCs via negative selection and stained the T cells with a dextramer pool. We sorted live, CD3+, CD8+ dextramer+ cells and performed RNA-, TCR-, and dextramer feature barcode sequencing (Fig. S5A). For certain samples where dextramer+ cell numbers were limiting, live CD3+ CD8+ dextramer- cells were also sorted, stained with cell hashing antibodies, and doped into the dextramer+ populations. Using this approach, we single-cell profiled CD8+ T-cells from nine samples across five distinct HLA-A*02:01+ SRSF2 mutant myeloid leukemia patients (Fig. 5A, Fig.S5B, and Table S3) yielding 75,343 high-quality T cells.
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| Contributor(s) |
Kim WJ, Cross E, de Neef E, Etxeberria I, Sabio E, Wang E, Lu SX, Belleville A, Fox N, Castro C, Zhang P, Fujino T, Lewis J, Rahman J, Zhang B, Stanley RF, Dewolf S, Chaligne R, Koppikar P, Molldrem J, Gigoux M, Merghoub T, Daniyan A, Greenbaum BF, Klebanoff C, Bradley RK, Abdel-Wahab O |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
May 22, 2024 |
| Last update date |
May 23, 2024 |
| Contact name |
Jahan Rahman |
| Organization name |
Memorial Sloan Kettering
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| Department |
Center for Hematologic Malignancies
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| Street address |
417 E 68th St
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| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL34284 |
Illumina NovaSeq X Plus (Homo sapiens) |
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| Samples (54)
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| GSM8286611 |
WJK-2719_SRSF2_2_RNA,SRSF2 Mutant |
| GSM8286612 |
WJK-2719_SRSF2_2_CITE,SRSF2 Mutant |
| GSM8286613 |
WJK-2719_SRSF2_2_TCR_VDJ,SRSF2 Mutant |
| GSM8286614 |
WJK-2726_SRSF2_3_RNA,SRSF2 Mutant |
| GSM8286615 |
WJK-2726_SRSF2_3_CITE,SRSF2 Mutant |
| GSM8286616 |
WJK-2726_SRSF2_3_TCR_VDJ,SRSF2 Mutant |
| GSM8286617 |
WJK-2765_SRSF2_5_replicate_1_RNA,SRSF2 Mutant |
| GSM8286618 |
WJK-2765_SRSF2_5_replicate_1_CITE,SRSF2 Mutant |
| GSM8286619 |
WJK-2765_SRSF2_5_replicate_1_TCR_VDJ,SRSF2 Mutant |
| GSM8286620 |
WJK-2765_SRSF2_5_replicate_2_RNA,SRSF2 Mutant |
| GSM8286621 |
WJK-2765_SRSF2_5_replicate_2_CITE,SRSF2 Mutant |
| GSM8286622 |
WJK-2765_SRSF2_5_replicate_2_TCR_VDJ,SRSF2 Mutant |
| GSM8286623 |
WJK-2854_SRSF2_7_RNA,SRSF2 Mutant |
| GSM8286624 |
WJK-2854_SRSF2_7_CITE,SRSF2 Mutant |
| GSM8286625 |
WJK-2854_SRSF2_7_TCR_VDJ,SRSF2 Mutant |
| GSM8286626 |
WJK-2859_SRSF2_9_RNA,SRSF2 Mutant |
| GSM8286627 |
WJK-2859_SRSF2_9_CITE,SRSF2 Mutant |
| GSM8286628 |
WJK-2859_SRSF2_9_TCR_VDJ,SRSF2 Mutant |
| GSM8286629 |
WJK-2864_SRSF2_10_RNA,SRSF2 Mutant |
| GSM8286630 |
WJK-2864_SRSF2_10_CITE,SRSF2 Mutant |
| GSM8286631 |
WJK-2864_SRSF2_10_TCR_VDJ,SRSF2 Mutant |
| GSM8286632 |
WJK-2866_SRSF2_12_RNA,SRSF2 Mutant |
| GSM8286633 |
WJK-2866_SRSF2_12_CITE,SRSF2 Mutant |
| GSM8286634 |
WJK-2866_SRSF2_12_TCR_VDJ,SRSF2 Mutant |
| GSM8286635 |
WJK-2866_SRSF2_13_RNA,SRSF2 Mutant |
| GSM8286636 |
WJK-2866_SRSF2_13_CITE,SRSF2 Mutant |
| GSM8286637 |
WJK-2866_SRSF2_13_TCR_VDJ,SRSF2 Mutant |
| GSM8286638 |
WJK-2870_ZRSR2_1_repeat_RNA,ZRSR2 Mutant |
| GSM8286639 |
WJK-2870_ZRSR2_1_repeat_CITE,ZRSR2 Mutant |
| GSM8286640 |
WJK-2870_ZRSR2_1_repeat_TCR_VDJ,ZRSR2 Mutant |
| GSM8286641 |
WJK-2870_ZRSR2_4_RNA,ZRSR2 Mutant |
| GSM8286642 |
WJK-2870_ZRSR2_4_CITE,ZRSR2 Mutant |
| GSM8286643 |
WJK-2870_ZRSR2_4_TCR_VDJ,ZRSR2 Mutant |
| GSM8286644 |
WJK-2876_ZRSR2_5_r1_RNA,ZRSR2 Mutant |
| GSM8286645 |
WJK-2876_ZRSR2_5_r1_CITE,ZRSR2 Mutant |
| GSM8286646 |
WJK-2876_ZRSR2_5_r1_TCR_VDJ,ZRSR2 Mutant |
| GSM8286647 |
WJK-2876_ZRSR2_5_r2_RNA,ZRSR2 Mutant |
| GSM8286648 |
WJK-2876_ZRSR2_5_r2_CITE,ZRSR2 Mutant |
| GSM8286649 |
WJK-2876_ZRSR2_5_r2_TCR_VDJ,ZRSR2 Mutant |
| GSM8286650 |
WJK-2876_ZRSR2_6_RNA,ZRSR2 Mutant |
| GSM8286651 |
WJK-2876_ZRSR2_6_CITE,ZRSR2 Mutant |
| GSM8286652 |
WJK-2876_ZRSR2_6_TCR_VDJ,ZRSR2 Mutant |
| GSM8286653 |
WJK-2878_HD12_rep1_RNA,Healthy Donor |
| GSM8286654 |
WJK-2878_HD12_rep1_CITE,Healthy Donor |
| GSM8286655 |
WJK-2878_HD12_rep1_TCR_VDJ,Healthy Donor |
| GSM8286656 |
WJK-2878_HD12_rep2_RNA,Healthy Donor |
| GSM8286657 |
WJK-2878_HD12_rep2_CITE,Healthy Donor |
| GSM8286658 |
WJK-2878_HD12_rep2_TCR_VDJ,Healthy Donor |
| GSM8286659 |
WJK-2878_HD13_repeat_RNA,Healthy Donor |
| GSM8286660 |
WJK-2878_HD13_repeat_CITE,Healthy Donor |
| GSM8286661 |
WJK-2878_HD13_repeat_TCR_VDJ,Healthy Donor |
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| Relations |
| BioProject |
PRJNA1114778 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE268157_RAW.tar |
369.4 Mb |
(http)(custom) |
TAR (of CSV) |
SRA Run Selector |
| Raw data are available in SRA |
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