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CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target
Quy Le, … , Keith R. Loeb, Soheil Meshinchi
Quy Le, … , Keith R. Loeb, Soheil Meshinchi
Published September 22, 2022
Citation Information: J Clin Invest. 2022;132(22):e157101. https://doi.org/10.1172/JCI157101.
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Research Article Oncology Article has an altmetric score of 11

CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target

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Abstract

The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML) and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G-fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, folate receptor α (FOLR1), and demonstrated their preclinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.

Authors

Quy Le, Brandon Hadland, Jenny L. Smith, Amanda Leonti, Benjamin J. Huang, Rhonda Ries, Tiffany A. Hylkema, Sommer Castro, Thao T. Tang, Cyd N. McKay, LaKeisha Perkins, Laura Pardo, Jay Sarthy, Amy K. Beckman, Robin Williams, Rhonda Idemmili, Scott Furlan, Takashi Ishida, Lindsey Call, Shivani Srivastava, Anisha M. Loeb, Filippo Milano, Suzan Imren, Shelli M. Morris, Fiona Pakiam, Jim M. Olson, Michael R. Loken, Lisa Brodersen, Stanley R. Riddell, Katherine Tarlock, Irwin D. Bernstein, Keith R. Loeb, Soheil Meshinchi

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Figure 3

Transcriptional profile of C/G-CB cells in EC coculture recapitulates primary C/G AML.

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Transcriptional profile of C/G-CB cells in EC coculture recapitulates pr...
(A) Unsupervised clustering by uniform manifold and projection (UMAP) analysis of C/G-CB and GFP-CB cells in reference to primary AML samples. Dashed circle indicates C/G-CB cells cocultured with ECs at week 6 and 12 time points. Normal bone marrow (NBM, n = 68); KMT2A (n = 319); RUNX1-RUNX1T1 (n = 157); CBFB-MYH11 (n = 120); other (n = 444); CBFA2T3-GLIS2 (n = 39). Primary patient data are described in Smith et al. (8). For cultured cells, n = 4 technical replicates for C/G-CB cells in EC coculture at week; n = 3 technical replicates for all other groups. (B) Top: Expression of ERG, BMP2, and GATA1 in GFP-CB versus C/G-CB cells over weeks in EC and MC conditions as well as in C/G-fusion-positive primary versus NBM samples. Bottom: Single-sample gene set enrichment (ssGSEA) scores of Hedgehog, TGF-β, and WNT signaling pathways for GFP-CB versus C/G-CB cells and NBM samples versus primary-fusion-positive samples. CBFA2T3-GLIS2 primary samples (n = 39); NBM samples (n = 68). For cultured cells, n = 4 technical replicates for C/G-CB cells in EC coculture at week; n = 3 technical replicates for all other groups. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 by unpaired, 2-sided, nonparametric Wilcoxon’s rank-sum test, analyzing differences in expression between C/G-CB in EC or MC conditions and GFP controls in EC or MC conditions, and differences between primary C/G AML samples and healthy NBM. (C) Heatmap of differentially expressed genes in C/G-CB versus GFP-CB cells in EC coculture or MC. (D) GSEA plots of C/G and HSC signature genes comparing C/G-CB cells in EC coculture versus MC at week 6 of culture. (E) Pathways that are upregulated (left) and downregulated (right) in C/G-CB cells in EC coculture compared with MC. (C–E) n = 4 technical replicates for C/G-CB cells in EC coculture at week 6; n = 3 technical replicates for all other groups.

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