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

Abstract

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.

CDK9 recruits HUWE1 E3 ligase to degrade RARα in a kinase independent manner and offers therapeutic opportunities for cutaneous T-cell lymphoma

“…2c), which was reinforced by cell-cycle analysis showing elevated G2-M and S-phase genes (Fig. 2g) 39,40 .…”

Spatially-Resolved Transcriptomics Define Clinically Relevant Subsets of Macrophages in Diffuse Large B-cell Lymphoma

“…While further validation is required for C1Q+ macrophages in DLBCL, C1Q is a promising prognostic marker and therapeutic target in other hematological malignancies. High C1Q expression in macrophages-like leukemia cells has been associated with extramedullary infiltration and poor prognosis in acute myeloid leukemia (45). The other negatively prognostic signature in our study was MacroSig8 (Relapsed-DLBCL), which maps to IL1B pro-inflammatory monocytes with pro-tumorigenic effects (46).…”

Decoding leukemia at the single-cell level: clonal architecture, classification, microenvironment, and drug resistance

“…Also, C1Q is a great therapeutic target. [ 62 ] AML scRNA-seq NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients, and increased expression of growth and survival genes in monocytes. NFIC knockdown in an ex vivo mouse a pre-leukemic stem cell model decreased their growth and colony formation and increased expression of myeloid differentiation markers Gr1 and Mac1.…”