CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity.
CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity.
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DOI：
10.1038/ncomms12320
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发表时间：
2016-07-27
影响因子：
16.6
通讯作者：
Fry TJ
中科院分区：
文献类型：
--
作者：
Jacoby E;Nguyen SM;Fountaine TJ;Welp K;Gryder B;Qin H;Yang Y;Chien CD;Seif AE;Lei H;Song YK;Khan J;Lee DW;Mackall CL;Gardner RA;Jensen MC;Shern JF;Fry TJ
针对CD19 B细胞系受体的嵌合抗原受体(CAR)表达的T细胞过继免疫治疗在复发性前B细胞急性淋巴细胞白血病(ALL)中显示出显着的成功。持续存在的CAR-T细胞对CD19产生持续的压力，这可能会驱动独特的耐药机制。Pre-B ALL起源于承诺的Pre-B细胞或更早的祖细胞，具有重新编程进入其他造血谱系的潜力。在这里，我们报告了CD19CAR治疗后患者的谱系标志物的变化，包括髓系转换。利用小鼠ALL模型，我们研究了CD19 CAR-T细胞的长期效应，并证明了部分或全部谱系转换是CAR耐药的一致机制，这取决于潜在的致癌基因驱动因素。Pax5或EBF1的缺失概括了CD19汽车加压期间发生的谱系重新编程。我们的发现确立了谱系转换是CAR抵抗的一种机制，揭示了前B细胞ALL遗传亚型的内在可塑性。针对CD19的CAR-T已经成功地用于各种B细胞恶性肿瘤，但患者最终可能会复发。在这里，作者表明，CD19CAR-T抗性在前B细胞ALL中可能是由于通过B细胞发育的主要调节因子的表观遗传学改变而诱导的髓系谱系转换。
Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL. CAR-T targeting CD19 have been successfully used in a variety of B-cell malignancies but patients may eventually relapse. Here, the authors show that CD19 CAR-T resistance in pre-B cell ALL can be due to the induction of a myeloid lineage switch through an epigenetic alterations in master regulators of B cell development.