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

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 an AML patient presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset which is enriched within cutis and existed in BM prior to EMI manifestations was identified and further verified in multiple AML patients. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of EMI patients that expressed high level of C1Q. RNA-sequencing and quantitative proteomics 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 MAFB, endowed leukemia cells with tissue-infiltration ability which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-gC1QR recognition and subsequent stimulation of TGF-β1. This cell-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as an adverse prognostic marker of AML which orchestrates cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.