C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse.
C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse.
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DOI：
10.1182/blood.2022017046
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发表时间：
2023-02-16
期刊：
影响因子：
20.3
通讯作者：
Lu, Ying
中科院分区：
文献类型：
--
作者：
Yang, Li-Xue;Zhang, Cheng-Tao;Yang, Meng-Ying;Zhang, Xue-Hong;Liu, Hong-Chen;Luo, Chen -Hui;Jiang, Yue;Wang, Zhang-Man;Yang, Zhong-Yin;Shi, Zhao -Peng;Yang, Yi-Ci;Wei, Ruo-Qu;Zhou, Li;Mi, Jun;Zhou, Ai -Wu;Yao, Zhi-Rong;Xia, Li;Yan, Jin-Song;Lu, Ying
C1Q+ 细胞代表高度组织浸润的白血病群体，可以重建 AML 的 EMI 表型。成纤维细胞通过 C1Q-球状 C1Q 受体识别和刺激转化生长因子 β1 合成来吸引 C1Q+ 白血病细胞。髓外浸润（EMI）是一种伴随表现，可能表明急性髓系白血病（AML）预后不良。其潜在机制仍知之甚少，治疗选择也有限。在这里，我们对一名患有广泛性皮肤白血病的 AML 患者的骨髓 (BM) 和 EMI 样本进行了单细胞 RNA 测序。在多例 AML 患者中发现并进一步验证了补体 C1Q+ 巨噬细胞样白血病亚群，该亚群在 EMI 表现之前在皮肤内富集并存在于 BM 中。基因组和转录分析揭示了表达高水平 C1Q 的 EMI 患者的突变和基因表达特征。 RNA 测序和定量蛋白质组分析揭示了 C1Q 从原发到复发的表达动态。单变量和多变量分析证明了 C1Q 表达的不良预后意义。从机制上讲，受转录因子MAF BZIP转录因子B调节的C1Q表达赋予白血病细胞组织浸润能力，可以在患者来源的异种移植和细胞系来源的异种移植模型中建立显着的皮肤或胃肠道EMI结节。成纤维细胞通过 C1Q-球状 C1Q 受体识别和随后的转化生长因子 β1 刺激吸引 C1Q+ 白血病细胞的迁移。这种细胞间通讯也有助于 C1Q+ 白血病细胞在化疗应激下的存活。因此，C1Q 作为预后不良的 AML 的标志物，通过与成纤维细胞通讯来协调癌症浸润途径，并代表了 EMI 的一个引人注目的治疗靶点。急性髓系白血病（AML）患者的髓外浸润（EMI）与不良预后相关。 Yang 等人研究了一名患有广泛性皮肤白血病的患者，并证明了皮肤和骨髓内存在补体 C1Q+ 细胞亚群。随后的研究表明，C1Q 过度表达常见于伴有 EMI 和复发的 AML 中。 C1Q 既是 AML 的不良预后标志物，又与 EMI 相关，提供了潜在的新治疗靶点。
C1Q+ cells represent a highly tissue-infiltrative leukemia population and could reconstitute EMI phenotype of AML. Fibroblast attracts C1Q+ leukemia cell via C1Q–globular C1Q receptor recognition and stimulation of transforming growth factor β1 synthesis. Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line–derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q–globular C1Q receptor recognition and subsequent stimulation of transforming growth factor β1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI. Extramedullary infiltration (EMI) in patients with acute myeloid leukemia (AML) is associated with poor prognosis. Yang et al investigated a patient with extensive leukemia cutis and demonstrated a complement C1Q+ subset of cells within the skin and the bone marrow. Subsequent studies reveal that C1Q overexpression is commonly seen in AML with EMI and relapse. C1Q is both a poor prognostic marker in AML and is associated with EMI, offering a potential novel therapeutic target.
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影响因子：
50.3
作者：
Dong, Lihui;Chen, Chuanyuan;Han, Dali
通讯作者：
Han, Dali
影响因子：
5.8
作者：
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45.3
作者：
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影响因子：
3.1
作者：
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通讯作者：
Friis, Lone Smidstrup
影响因子：
11.4
作者：
Kelly, LM;Englmeier, U;Graf, T
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Graf, T