由骨髓来源的间充质基质细胞 (MSC) 产生的癌症相关成纤维细胞 (CAF) 在 B 前体急性淋巴细胞白血病 (B-ALL) 中最为突出。我们之前已经证明，CAF 的形成是通过暴露于活性氧诱导化疗而触发的，并且 CAF 通过隧道纳米管向癌细胞提供线粒体来支持化疗耐药性。在本研究中，我们发现将 MSC 暴露于 ALL 细胞系、患者来源的异种移植物和原代细胞或其条件培养基也可以触发 CAF 形成。通过在细胞系中进行批量 RNA 测序，我们发现 MSC 向 CAF 的转变伴随着强大的干扰素途径反应，并且我们已经在原代细胞中验证了这一发现。使用共聚焦显微镜和流式细胞术，我们确定 MSC 摄取白血病细胞来源的线粒体 dsRNA 作为 MSC 向 CAF 转变的直接触发因素。我们发现，通过低剂量乙锭或线粒体转录抑制剂 IMT1 处理来抑制 ALL 细胞中 dsRNA 的形成，或者通过 100°C 暴露在条件培养基中降解 dsRNA，可以消除 ALL 条件培养基刺激 MSC 向 CAF 转变的能力。我们的数据揭示了一种新颖且先前未描述的机制，癌细胞通过该机制在基质细胞中诱导 CAF 表型，显示 B-ALL 细胞如何直接诱导骨髓内先前描述的生态位介导的保护。版权所有 © 2024 美国血液学会。

Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, patient-derived xenografts and primary cells or their conditioned media can also trigger CAF formation. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the take-up of leukaemia cell-derived mitochondrial dsRNA by MSC as a proximate trigger for the MSC to CAF transition. We show that inhibition of dsRNA formation in ALL cells by treatment with low-dose ethidium or the mitochondrial transcription inhibitor IMT1 or degradation of dsRNA in conditioned media by 100°C exposure ablates the ability of the ALL conditioned media to stimulate MSC to CAF transition. Our data reveal a novel and previously undescribed mechanism by which cancer cells induce a CAF phenotype in stromal cells, showing how B-ALL cells can directly induce the previously described niche-mediated protection within the bone marrow.Copyright © 2024 American Society of Hematology.