CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.
CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.
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DOI：
10.1172/jci157101
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发表时间：
2022-11-15
影响因子：
15.9
通讯作者：
Meshinchi, Soheil
中科院分区：
文献类型：
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作者：
Le, Quy;Hadland, Brandon;Smith, Jenny L.;Leonti, Amanda;Huang, Benjamin J.;Ries, Rhonda;Hylkema, Tiffany A.;Castro, Sommer;Tang, Thao T.;McKay, Cyd N.;Perkins, LaKeisha;Pardo, Laura;Sarthy, Jay;Beckman, Amy K.;Williams, Robin;Idemmili, Rhonda;Furlan, Scott;Ishida, Takashi;Call, Lindsey;Srivastava, Shivani;Loeb, Anisha M.;Milano, Filippo;Imren, Suzan;Morris, Shelli M.;Pakiam, Fiona;Olson, Jim M.;Loken, Michael R.;Brodersen, Lisa;Riddell, Stanley R.;Tarlock, Katherine;Bernstein, Irwin D.;Loeb, Keith R.;Meshinchi, Soheil
CBFA 2 T3-GLIS 2（C/G）融合是主要见于婴儿和幼儿的隐性易位的产物，并与令人沮丧的结局相关。在这里，我们证明了C/G致癌融合蛋白的表达促进了人脐带血造血干细胞和祖细胞（CB HSPCs）在内皮细胞共培养系统中的转化，该系统概括了C/G急性髓细胞白血病（AML）的转录组、形态学和免疫表型，并在异种移植模型中诱导高度侵袭性白血病。询问C/G-CB细胞和原发性C/G AML的转录组鉴定了作为治疗的潜在靶标的C/G融合特异性基因的文库。我们开发了针对其中一个靶点叶酸受体α（FOLR 1）的嵌合抗原受体（CAR）T细胞，并使用体外和异种移植模型证明了其对C/G AML的临床前疗效。FOLR 1也在肾和肺上皮中表达，引起了对这种疗法的临床应用必须解决的毒性的担忧。我们的研究结果强调了内皮小生境在促进C/G转导的CB HSPCs的白血病转化中的作用。此外，这项工作具有广泛的意义适用于各种致癌融合驱动的儿科白血病的白血病发生的研究，提供了一个强大的和易于处理的模型系统，以表征白血病发生的分子机制，并确定疾病诊断和治疗靶点的生物标志物。
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.
影响因子：
11.4
作者：
通讯作者：
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