Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Sci Adv. 2023 May 10;9(19):eadf8549. doi: 10.1126/sciadv.adf8549.
Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry mutations, causing mTORC1 hyperactivation and uncontrolled cell growth. mTORC1 inhibitors stabilize lung function; however, sustained efficacy requires long-term administration, and some patients fail to tolerate or respond to therapy. Although the genetic basis of LAM is known, mechanisms underlying LAM pathogenesis remain elusive. We integrated single-cell RNA sequencing and single-nuclei ATAC-seq of LAM lungs to construct a gene regulatory network controlling the transcriptional program of LAM cells. We identified activation of uterine-specific HOX-PBX transcriptional programs in pulmonary LAM cells as regulators of cell survival depending upon HOXD11-PBX1 dimerization. Accordingly, blockage of HOXD11-PBX1 dimerization by HXR9 suppressed LAM cell survival in vitro and in vivo. PBX1 regulated STAT1/3, increased the expression of antiapoptotic genes, and promoted LAM cell survival in vitro. The HOX-PBX gene network provides promising targets for treatment of LAM/TSC mTORC1-hyperactive cancers.
淋巴管平滑肌瘤病（LAM）是一种罕见的、进行性的肺部疾病，主要影响女性。LAM 细胞携带 突变，导致 mTORC1 过度激活和不受控制的细胞生长。mTORC1 抑制剂稳定肺功能；然而，持续的疗效需要长期给药，并且一些患者无法耐受或对治疗无反应。尽管 LAM 的遗传基础是已知的，但 LAM 发病机制的机制仍然难以捉摸。我们整合了 LAM 肺部的单细胞 RNA 测序和单核 ATAC-seq，构建了一个控制 LAM 细胞转录程序的基因调控网络。我们发现，肺部 LAM 细胞中子宫特异性 HOX-PBX 转录程序的激活是细胞存活的调节剂，取决于 HOXD11-PBX1 二聚体的形成。因此，HXR9 通过阻断 HOXD11-PBX1 二聚体抑制了体外和体内 LAM 细胞的存活。PBX1 调节 STAT1/3，增加抗凋亡基因的表达，并促进体外 LAM 细胞的存活。HOX-PBX 基因网络为治疗 LAM/TSC mTORC1 过度活跃的癌症提供了有希望的靶点。
