4.7 Article

C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse

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BLOOD
卷 141, 期 7, 页码 766-786

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AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2022017046.

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Single-cell RNA sequencing revealed a subset of complement C1Q(+) macrophage-like leukemia cells enriched in the skin of AML patients with EMI. C1Q expression was associated with adverse prognosis and mediated communication with fibroblasts, promoting tissue infiltration and survival under chemotherapy stress. Hence, C1Q serves as a marker for poor prognosis in AML and represents a promising therapeutic target for EMI.
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 beta 1. 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.

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