Fan Changxu, Wu Jun, Barisas Derek A G, Xing Xiaoyun, Kwon Yoojung, Choi Kyunghee, Wang Ting
Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States.
The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, United States.
J Immunol. 2025 Jun 1;214(6):1384-1397. doi: 10.1093/jimmun/vkaf026.
Increased myeloid lineage production, termed myeloid skewing, leading to decreased tumor immunity, is a hallmark of aberrant hematopoiesis associated with cancer. It is believed that myeloid skewing may occur at the hematopoietic stem and progenitor cells (HSPCs) level to elicit hematopoietic changes. However, our understanding of the underlying molecular mechanisms remains incomplete. Here, we characterize the transcriptional and chromatin accessibility landscapes of bone marrow and splenic hematopoietic progenitors in the MMTV-PyMT mouse model of breast cancer using single-cell ATAC + RNA sequencing. We show that HSPCs in the bone marrow (BM) of the tumor-bearing mice show a modest upregulation of the myeloid-bias transcriptional signature without significant chromatin accessibility changes. By contrast, dendritic cell (DC) progenitors exhibit the most prominent transcriptional and chromatin changes, showing a signature of STAT3, CEBP, and non-DC myeloid gene activation. Compared to BM, splenic HSPCs exhibit a Notch signaling signature associated with erythroid commitment rather than further upregulation of the myeloid-bias signature. In addition, we also identify a cluster of splenic HSPCs in tumor-bearing animals with a transcriptional signature of mobilization. Our paired chromatin data suggest that AP-1 factors play a crucial role in driving this HSPC mobilization signature. Overall, we provide a comprehensive dataset for understanding the hematopoietic consequences of cancer.
髓系谱系生成增加，即髓系偏向，导致肿瘤免疫降低，是与癌症相关的异常造血的一个标志。据信，髓系偏向可能发生在造血干细胞和祖细胞（HSPCs）水平，以引发造血变化。然而，我们对其潜在分子机制的理解仍不完整。在这里，我们使用单细胞ATAC + RNA测序对乳腺癌的MMTV-PyMT小鼠模型中的骨髓和脾脏造血祖细胞的转录和染色质可及性图谱进行了表征。我们发现，荷瘤小鼠骨髓（BM）中的HSPCs显示出髓系偏向转录特征的适度上调，但染色质可及性没有显著变化。相比之下，树突状细胞（DC）祖细胞表现出最显著的转录和染色质变化，显示出STAT3、CEBP和非DC髓系基因激活的特征。与BM相比，脾脏HSPCs表现出与红系分化相关的Notch信号特征，而不是髓系偏向特征的进一步上调。此外，我们还在荷瘤动物中鉴定出一群具有动员转录特征的脾脏HSPCs。我们的配对染色质数据表明，AP-1因子在驱动这种HSPC动员特征中起关键作用。总体而言，我们提供了一个全面的数据集，以了解癌症对造血的影响。
