Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padova, 35128, Italy.
Onco-Hematology, Department of Oncology, Veneto Institute of Oncology, IOV-IRCCS, Padua, 31033, Italy.
Cell Commun Signal. 2024 Oct 21;22(1):510. doi: 10.1186/s12964-024-01877-3.
Myelofibrosis (MF) is a complex myeloproliferative neoplasm characterized by abnormal hematopoietic stem cell proliferation and subsequent bone marrow (BM) fibrosis. First documented in the late 19th century, MF has since been extensively studied to unravel its pathophysiology, clinical phenotypes, and therapeutic interventions. MF can be classified into primary and secondary forms, both driven by mutations in genes such as JAK2, CALR, and MPL, which activate the JAK-STAT signaling pathway. These driver mutations are frequently accompanied by additional non-driver mutations in genes like TET2, SRSF2, and TP53, contributing to disease complexity. The BM microenvironment, consisting of stromal cells, extracellular matrix, and cytokines such as TGF-β and TNF-α, plays a critical role in fibrosis and aberrant hematopoiesis. Clinically, MF manifests with symptoms ranging from anemia, splenomegaly, and fatigue to severe complications such as leukemic transformation. Splenomegaly, caused by extramedullary hematopoiesis, leads to abdominal discomfort and early satiety. Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches. Allogeneic hematopoietic stem cell transplantation remains the only curative option, though it is limited to younger, high-risk patients. Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape. Spatially Resolved Transcriptomics (SRT) has revolutionized the study of gene expression within the spatial context of tissues, providing unprecedented insights into cellular heterogeneity, spatial gene regulation, and microenvironmental interactions, including stromal-hematopoietic dynamics. SRT enables high-resolution mapping of gene expression in the BM and spleen, revealing molecular signatures, spatial heterogeneity, and pathological niches that drive disease progression. These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a "tumor surrogate." By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease.
骨髓纤维化（MF）是一种复杂的骨髓增生性肿瘤，其特征为异常造血干细胞增殖，随后发生骨髓（BM）纤维化。MF 于 19 世纪末首次被记录，此后对其发病机制、临床表型和治疗干预进行了广泛研究。MF 可分为原发性和继发性，两者均由 JAK2、CALR 和 MPL 等基因的突变驱动，这些突变激活了 JAK-STAT 信号通路。这些驱动突变常伴有 TET2、SRSF2 和 TP53 等基因的其他非驱动突变，导致疾病的复杂性。由基质细胞、细胞外基质和 TGF-β和 TNF-α等细胞因子组成的 BM 微环境在纤维化和异常造血中起着关键作用。临床上，MF 表现为贫血、脾肿大、疲劳等症状，严重时还会出现白血病转化等并发症。脾肿大是由骨髓外造血引起的，导致腹部不适和早饱。目前的治疗策略包括 Ruxolitinib 等 JAK 抑制剂，这些抑制剂靶向 JAK-STAT 通路，同时还包括输血、促红细胞生成素刺激剂等支持性治疗，并正在开发联合治疗方法。异基因造血干细胞移植仍然是唯一的治愈方法，但仅限于年轻、高危患者。最近批准的 JAK 抑制剂，包括 Fedratinib、Pacritinib 和 Momelotinib，扩大了治疗范围。空间分辨转录组学（SRT）改变了组织空间背景下基因表达的研究，为细胞异质性、空间基因调控和微环境相互作用（包括基质-造血动态）提供了前所未有的见解。SRT 能够在 BM 和脾脏中高分辨率地绘制基因表达图谱，揭示驱动疾病进展的分子特征、空间异质性和病理龛位。这些技术阐明了脾脏在 MF 中的作用，突出了其转变为异常造血活性、纤维化变化和免疫细胞浸润的场所，充当“肿瘤替代物”。通过对 BM 和脾脏中不同细胞群和分子改变进行分析，SRT 有助于更深入地了解 MF 的发病机制，帮助确定新的治疗靶点和生物标志物。最终，将空间转录组学纳入 MF 研究有望提高诊断精度和治疗创新，解决该疾病的多方面挑战。
