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| Status |
Public on Aug 08, 2024 |
| Title |
Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
In contrast to patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL), patients with acute myeloid leukemia (AML) have not yet benefited from recent advances in targeted immunotherapy. Repurposing immunotherapies that have been successfully used to target other hematological malignancies could, in case of a shared target antigen, represent a promising opportunity to expand the immunotherapeutic options for AML. Here, we evaluated the expression of CD19 in a large pediatric AML cohort, assessed the ex vivo AML killing efficacy of CD19-directed immunotherapies, and characterized the bone marrow immune microenvironment in pediatric AML, BCP-ALL, and non-leukemic controls. Out of 167 newly diagnosed de novo pediatric AML patients, 18 patients (11%) had CD19+ AML, with 61% carrying the translocation t(8;21)(q22;q22). Among CD19+ samples, we observed a continuum of CD19 expression levels on AML cells. In individuals exhibiting unimodal and high CD19 expression, the antigen was consistently present on nearly all CD34+CD38- and CD34+CD38+ subpopulations. In ex vivo AML-T cell co-cultures, blinatumomab demonstrated substantial AML killing, with an efficacy similar to BCP-ALL. In addition, CAR T cells could effectively eliminate CD19+ AML cells ex vivo. Furthermore, our immunogenomic assessment of the bone marrow immune microenvironment of newly diagnosed pediatric t(8;21) AML revealed that T- and NK cells had a less exhausted and senescent phenotype in comparison to pediatric BCP-ALL. Altogether, our study underscores the promise of CD19-directed immunotherapies for the treatment of pediatric CD19+ AML.
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| Overall design |
In this study, we compared the bulk RNA-seq gene expression profiles of pediatric t(8;21) AML patients (n=10), non-t(8;21) pediatric AML (n=30), non-leukemic controls (n=4; derived from another publication: PMID 37908360), and pediatric B cell precursor acute lymphoblastic leukemia patients (n=209). To acquire the gene expression profiles from these patient samples, total RNA was isolated from viably frozen bone marrow mononuclear cells (BMMCs; derived from BM aspirates), RNA-seq libraries were generated from 300 ng RNA, and sequenced with NovaSeq 6000 (2x150 bp; Illumina). After pre-processing, RNA-sequencing yielded 80-100 million raw reads. Reads were aligned to GRCh38 and gencode version 31. Downstream analysis was done as shown in our preprint: https://www.biorxiv.org/content/10.1101/2024.04.19.590200v1.
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Raw data not allowed to make the data publicly available due to informed consent restrictions; contact authors for these data
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| Web link |
https://haematologica.org/article/view/haematol.2024.285707
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| Contributor(s) |
Farnaz B, Joost K, Noa W, Olaf H |
| Citation(s) |
- Barneh F, Koedijk JB, Wijnen NE, Meulendijks T et al. Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia. Haematologica 2024 Dec 1;109(12):4131-4136. PMID: 39113654
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| Submission date |
Jun 18, 2024 |
| Last update date |
Aug 08, 2024 |
| Contact name |
Joost Koedijk |
| E-mail(s) |
j.b.koedijk@prinsesmaximacentrum.nl
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| Organization name |
Princess Máxima Center for Pediatric Oncology
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| Street address |
Heidelberglaan 25
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| City |
Utrecht |
| ZIP/Postal code |
3584 CS |
| Country |
Netherlands |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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