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Correction: A novel approach for relapsed/refractory FLT3mut+acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib
Molecular Cancer ( IF 27.7 ) Pub Date : 2022-06-23 , DOI: 10.1186/s12943-022-01566-0
Ke-Xin Li 1 , Hui-Yang Wu 1 , Wan-Ying Pan 1 , Meng-Qi Guo 1 , De-Zhi Qiu 1 , Yan-Jie He 1 , Yu-Hua Li 1 , Dong-Hua Yang 2 , Yu-Xian Huang 1
Affiliation  

Correction: Mol Cancer 21, 66 (2022)

https://doi.org/10.1186/s12943-022-01541-9

Following publication of the original article [1], the authors identified minor errors in Figs. 3, 4, 5 and Additional file 5: Figure S5, and Additional file 14: Table S4; specifically:

  • Fig. 3B: 'Control' panel was originally a duplicate of the Giliteritinib panel; this has been replaced by the correct images

  • Fig. 4A: The ordinate label was incorrectly listed as 'FSC'; the correct listing is 'count'

  • Fig. 4B and Fig. 4C: the column color of the statistical histograms in did not originally correspond to the legend color; this has been corrected

  • Fig. 5D: incorrect images were used for the control group and +G group (rows 1 and 2); these have been replaced by the correct images

  • Additional file 5: Figure S5A: incorrect image used for the MICB band; this has been replaced with the correct image

  • Additional file 14: Table S4: The sequences of forward/reverse primers for Rel A, Rel B and c-Rel were found to be erroneously completed; this has been corrected

The corrected figures and table are given here. The correction does not have any effect on the final conclusions of the paper. The original article has been corrected.

Fig. 3
figure 1

The combination of FLT3scFv/NKG2D-CAR T cells and gilteritinib act synergistically on mediating the regression of AML in a xenograft mouse model. A Schema of establishing the AML xenograft mouse model. NSG mice were injected with MOLM-13 luciferase-expressing cells (2 × 106 cells) via the tail vein. On day 7, gilteritinib was dissolved in 4% DMSO and administered via intraperitoneal (i.p.) injection at a dose of 15 mg/kg, which was continued 5 days/week for 3 weeks in Groups 2 and 4. On day 8, a single dose of FLT3scFv/NKG2D-CAR T cells (2.5 × 106 cells) was injected via the tail vein in Groups 3 and 4 (n = 4 mice/group). B Leukaemia progression was monitored by serial bioluminescent (BL) imaging using an IVIS Lumina imaging system following D-luciferin substrate administration (0.3 mg/g body weight, IP). The scale (right) shows the upper and lower BL imaging thresholds at each analysis time point (days 7, 14, 21, and 28). C AML burden was assessed by quantification of BL radiance obtained as photon/sec/cm2/sr in the target zone encompassing the entire body of each mouse, and the AML burden was significantly reduced in mice treated with FLT3scFv/NKG2D-CAR T cells alone and in combination with gilteritinib. The waterfall plot shows the ∆BL value (upper-increase/below-decrease) as absolute BL values obtained from each mouse between day 7 and day 14 after tumour inoculation. D Kaplan–Meier survival curves showed the survival of AML mice was significantly improved with CAR T cell monotherapy (p < 0.05 compared with gilteritinib monotherapy) and with combination therapy (p < 0.05 compared with CAR T cell monotherapy). The in vivo data shown are derived from two independent experiments with T cells provided from 2 different donors. E Immunofluorescence staining showed that the distribution of CAR T cells in the bone marrow of AML mice was significantly enhanced following combination with gilteritinib treatment. The diagram shows the MFI of GFP + CAR T cells from n = 3 mice in each group as assessed with ImageJ. MFI, mean fluorescence intensity. GFP, green fluorescent protein. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001

Full size image
Fig. 4
figure 2

Gilteritinib upregulated the expression of NKG2DLs and FLT3 in MOLM-13 and MV4-11 cell lines. A Flow cytometry analysis showed that the expression of NKG2DLs (MICA/B and ULBP1/3) in MOLM-13 and MV4-11 cells was significantly upregulated with gilteritinib treatment. Histograms show NKG2DL expression on MOLM-13 cells and MV4-11 cells in the absence (grey) and presence (black) of IC25-gilteritinib for 24 h. Inset numbers show the ratio in MFI of treated/nontreated cells. B Western blotting (left) showed that the protein levels of all NKG2DLs in the MOLM-13 cell line were significantly increased with gilteritinib treatment, but in the MV4-11 cell line, only the MICA and ULBP1 levels were upregulated. The diagrams (right) show the relative expression as the grey intensity ratio of the NKG2DL (MICA ~ B, ULBP1 ~ 2) protein band to the internal control (C) Flow cytometry analysis of FLT3 expression on cell lines (MOLM-13 and MV4-11) with or without gilteritinib treatment. The histograms show FLT3 expression in MOLM-13 and MV4-11 cells treated without gilteritinib (0), 24-h IC25 gilteritinib (1), and 24-h IC50 gilteritinib (2). D Western blotting (left) indicated that FLT3 expression in both cell lines was significantly upregulated by gilteritinib pre-treatment. The diagrams (right) show the relative expression as the grey intensity ratio of the FLT3 protein band to the internal control. G, gilteritinib; FITC, fluorescein isothiocyanate; MFI, mean fluorescence intensity. ns, not significant. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001

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Fig. 5
figure 3

Gilteritinib upregulated the expression of NKG2DLs and FLT3 in AML cells from patients with FLT3mut+ and FLT3mut− AML and in the bone marrow of xenograft mouse models. A-B Flow cytometry analysis indicated that NKG2DL expression in AML cells from patients with FLT3mut+ or FLT3mut− AML was significantly elevated with gilteritinib treatment. Histograms show NKG2DL expression on FLT3mut+ or FLT3mut− AML in the absence (grey) and presence (black) of gilteritinib for 24 h. Inset numbers showed the ratio in MFI of treated/non-treated cells. C The upregulation of FLT3 following gilteritinib treatment was only detected in cells from patients with FLT3mut+ AML and not in cells from patients with FLT3mut− AML. Histograms show FLT3 expression on FLT3mut+ or FLT3mut− AML in the absence (grey) and presence (black) of gilteritinib for 24 h. Inset numbers showed the ratio in MFI of treated/non-treated cells. D In xenograft models, bone marrow immunofluorescence staining showed the density of NKG2DL ULBP1 and FLT3 cells. E The diagram showed the MFIs of NKG2DL ULBP1 (green) and FLT3 (red) measured by ImageJ from n = 3 mice in each group. G, gilteritinib; MFI, mean fluorescence intensity. ns, not significant. * p < 0.05; ** p < 0.01; *** p < 0.001

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  1. Li K, Wu H, Pan Wy, et al. A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib. Mol Cancer. 2022;21:66. https://doi.org/10.1186/s12943-022-01541-9.

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Author notes

  1. Ke-xin Li and Hui-yang Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China

    Ke-xin Li, Hui-yang Wu, Wan-ying Pan, Meng-qi Guo, De-zhi Qiu, Yan-jie He, Yu-hua Li & Yu-xian Huang

  2. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, 11439, USA

    Dong-Hua Yang

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Correspondence to Dong-Hua Yang or Yu-xian Huang.

Additional file 5: Figure S5A.

The transcriptional role of NF-κB2 in NKG2DL expression.

Additional file 14: Table S4.

The sequences of forward/reverse primers for target genes.

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Li, Kx., Wu, Hy., Pan, Wy. et al. Correction: A novel approach for relapsed/refractory FLT3mut+acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib. Mol Cancer 21, 134 (2022). https://doi.org/10.1186/s12943-022-01566-0

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中文翻译：
更正：复发/难治性FLT3mut+急性髓系白血病的新方法：双特异性FLT3scFv/NKG2D-CAR T细胞与gilteritinib联合的协同效应

更正：Mol Cancer 21, 66 (2022)

https://doi.org/10.1186/s12943-022-01541-9

在发表原始文章 [1] 后，作者发现了图 1 和 2 中的小错误。3、4、5和附加文件5：图S5，和附加文件14：表S4；具体来说：

  • 图 3B：“对照”组最初是吉立替尼组的副本；这已被正确的图像取代

  • 图 4A：纵坐标标签被错误地列为“FSC”；正确的列表是“计数”

  • 图4B和图4C：统计直方图的列颜色原本与图例颜色不对应；这已得到纠正

  • 图 5D：对照组和 +G 组（第 1 行和第 2 行）使用了错误图像；这些已被正确的图像取代

  • 附加文件 5：图 S5A：MICB 波段使用的图像不正确；这已替换为正确的图像

  • 附加文件14：表S4：发现Rel A、Rel B和c-Rel的正向/反向引物序列错误补全；这已得到纠正

此处给出了更正的数字和表格。更正对论文的最终结论没有任何影响。原文章已更正。

图 3
图1

FLT3scFv/NKG2D-CAR T 细胞和 gilteritinib 的组合在介导异种移植小鼠模型中的 AML 消退方面具有协同作用。建立AML 异种移植小鼠模型的示意图。NSG小鼠通过尾静脉注射MOLM-13荧光素酶表达细胞（2×10 6 个细胞）。第 7 天，将 gilteritinib 溶解在 4% DMSO 中，通过腹膜内 (ip) 注射给药，剂量为 15 mg/kg，第 2 组和第 4 组连续 5 天/周，共 3 周。第 8 天，单次给药在第 3 组和第 4 组（ n  = 4 只小鼠/组）中通过尾静脉注射剂量的 FLT3scFv/NKG2D-CAR T 细胞（2.5 × 10 6 个细胞）。乙在 D-荧光素底物给药 (0.3 mg/g 体重，IP) 后，使用 IVIS Lumina 成像系统通过串行生物发光 (BL) 成像监测白血病进展。刻度（右）显示每个分析时间点（第 7、14、21 和 28 天）的上下 BL 成像阈值。C AML 负担通过在目标区域（包括每只小鼠的整个身体）中以光子/秒/cm2/sr 获得的 BL 辐射的量化来评估，并且仅用 FLT3scFv/NKG2D-CAR T 细胞治疗的小鼠的 AML 负担显着降低并与gilteritinib联合使用。瀑布图显示 ΔBL 值（上增加/下减少）作为肿瘤接种后第 7 天至第 14 天从每只小鼠获得的绝对 BL 值。DKaplan-Meier 生存曲线显示，CAR T 细胞单药治疗（与 gilteritinib 单药治疗相比p  < 0.05）和联合治疗（与 CAR T 细胞单药治疗相比p < 0.05）显着提高了 AML 小鼠的生存率 。显示的体内数据来自两个独立的实验，其中 T 细胞由 2 个不同的供体提供。E免疫荧光染色显示，与gilteritinib联合治疗后，AML小鼠骨髓中的CAR T细胞分布显着增强。 该图显示了使用 ImageJ 评估的每组n = 3 只小鼠的 GFP + CAR T 细胞的 MFI 。MFI，平均荧光强度。GFP，绿色荧光蛋白。* p < 0.05; ** p  < 0.01; *** p  < 0.001；**** p  < 0.0001

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图 4
图 2

Gilteritinib 上调 MOLM-13 和 MV4-11 细胞系中 NKG2DLs 和 FLT3 的表达。流式细胞仪分析显示，在 MOLM-13 和 MV4-11 细胞中 NKG2DLs（MICA/B 和 ULBP1/3）的表达在 gilteritinib 治疗后显着上调。直方图显示在 IC25-gilteritinib 不存在（灰色）和存在（黑色）24 小时时 MOLM-13 细胞和 MV4-11 细胞上的 NKG2DL 表达。插图数字显示处理/未处理细胞的 MFI 比率。乙Western blotting（左）显示，在 gilteritinib 处理后，MOLM-13 细胞系中所有 NKG2DLs 的蛋白质水平显着增加，但在 MV4-11 细胞系中，只有 MICA 和 ULBP1 水平上调。图（右）显示了作为 NKG2DL（MICA ~ B，ULBP1 ~ 2）蛋白条带与内部对照的灰度强度比的相对表达（C）细胞系（MOLM-13 和 MV4）上 FLT3 表达的流式细胞术分析-11) 有或没有 gilteritinib 治疗。直方图显示了未使用 gilteritinib (0)、24-h IC25 gilteritinib (1) 和 24-h IC50 gilteritinib (2) 处理的 MOLM-13 和 MV4-11 细胞中的 FLT3 表达。D蛋白质印迹（左）表明，两种细胞系中的 FLT3 表达均被 gilteritinib 预处理显着上调。图表（右）显示了作为 FLT3 蛋白条带与内部对照的灰度强度比的相对表达。G、吉特替尼；FITC，异硫氰酸荧光素；MFI，平均荧光强度。ns，不显着。* p  < 0.05；** p  < 0.01; *** p  < 0.001；**** p  < 0.0001

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图 5
图 3

Gilteritinib 上调来自 FLT3 mut+和 FLT3 mut- AML患者的 AML 细胞和异种移植小鼠模型骨髓中 NKG2DLs 和 FLT3 的表达。AB流式细胞术分析表明，来自 FLT3 mut+或 FLT3 mut- AML 患者的 AML 细胞中的 NKG2DL 表达在 gilteritinib 治疗后显着升高。直方图显示在gilteritinib不存在（灰色）和存在（黑色）24 小时时，FLT3 mut+或 FLT3 mut- AML 上的 NKG2DL 表达。插图数字显示了处理/未处理细胞的 MFI 比率。Cgilteritinib 治疗后 FLT3 的上调仅在 FLT3 mut+ AML 患者的细胞中检测到，而在 FLT3 mut- AML 患者的细胞中未检测到。直方图显示在gilteritinib不存在（灰色）和存在（黑色）24 小时时 FLT3 mut+或 FLT3 mut- AML 上的 FLT3 表达。插图数字显示了处理/未处理细胞的 MFI 比率。D在异种移植模型中，骨髓免疫荧光染色显示 NKG2DL ULBP1 和 FLT3 细胞的密度。E该图显示了由 ImageJ 从n测量的 NKG2DL ULBP1（绿色）和 FLT3（红色）的 MFI= 每组 3 只小鼠。G、吉特替尼；MFI，平均荧光强度。ns，不显着。* p  < 0.05；** p  < 0.01; *** p  < 0.001

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  1. Li K、Wu H、Pan Wy 等。一种治疗复发/难治性 FLT3 mut+急性髓系白血病的新方法：双特异性 FLT3scFv/NKG2D-CAR T 细胞和 gilteritinib 组合的协同作用。摩尔癌症。2022；21:66。https://doi.org/10.1186/s12943-022-01541-9。

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作者笔记

  1. Ke-xin Li 和 Hui-yang Wu 对这项工作做出了同样的贡献。

作者和附属机构

  1. 南方医科大学珠江医院血液科,广东广州 510282

    李克新、吴慧阳、潘万英、郭梦琪、邱德志、何艳杰、李玉华、黄玉贤

  2. 圣约翰大学药学与健康科学学院药学系，纽约皇后区，11439，美国

    杨东华

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与杨东华或黄玉贤的通信。

附加文件 5：图 S5A。

NF-κB2 在 NKG2DL 表达中的转录作用。

附加文件 14：表 S4。

目标基因的正向/反向引物序列。

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Li, Kx., Wu, Hy., Pan, Wy. 等。更正：一种治疗复发/难治性 FLT3 mut+急性髓细胞白血病的新方法：双特异性 FLT3scFv/NKG2D-CAR T 细胞与 gilteritinib 组合的协同作用。摩尔癌症 21, 134 (2022)。https://doi.org/10.1186/s12943-022-01566-0

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