Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA
Molecular and Cellular Oncology, LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, France Laboratory of Hematology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie Paris VI University, France.
Haematologica. 2016 Oct;101(10):1133-1143. doi: 10.3324/haematol.2016.146563.
Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. While most systemic mastocytosis patients suffer from an indolent disease variant, some present with more aggressive variants, collectively called "advanced systemic mastocytosis", which include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic, clonal non mast cell-lineage disease, and mast cell leukemia. Whereas patients with indolent systemic mastocytosis have a near normal life expectancy, patients with advanced systemic mastocytosis have a reduced life expectancy. Although cladribine and interferon-alpha are of benefit in a group of patients with advanced systemic mastocytosis, no curative therapy is available for these patients except possible allogeneic hematopoietic stem cell transplantation. Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. In addition, several additional signaling molecules involved in the abnormal proliferation of mast cells in systemic mastocytosis have been identified. These advances have led to a better understanding of the biology of advanced systemic mastocytosis and to the development of new targeted treatment concepts. Herein, we review the biology and pathogenesis of advanced systemic mastocytosis, with a special focus on novel molecular findings as well as current and evolving therapeutic options.
系统性肥大细胞增多症是一种异质性疾病，其特征是骨髓和其他器官/组织中积累了肿瘤性肥大细胞。超过 80%的系统性肥大细胞增多症患者检测到 KIT 突变，最常见的是 KIT D816V。虽然大多数系统性肥大细胞增多症患者患有惰性疾病变异体，但一些患者表现出更具侵袭性的变异体，统称为“晚期系统性肥大细胞增多症”，包括侵袭性系统性肥大细胞增多症、伴有相关血液学、克隆性非肥大细胞谱系疾病的系统性肥大细胞增多症和肥大细胞白血病。虽然惰性系统性肥大细胞增多症患者的预期寿命接近正常，但晚期系统性肥大细胞增多症患者的预期寿命缩短。虽然克拉屈滨和干扰素-α对一组晚期系统性肥大细胞增多症患者有益，但除了可能的异基因造血干细胞移植外，这些患者没有治愈性治疗方法。最近的研究还揭示了大多数晚期系统性肥大细胞增多症患者除了 KIT 突变之外的其他体细胞缺陷。这些缺陷包括 TET2、SRSF2、ASXL1、RUNX1、JAK2 和/或 RAS 突变，这些缺陷可能会对某些特定的伴有血液学肿瘤的系统性肥大细胞增多症的预后和生存产生不利影响。此外，还鉴定出了参与系统性肥大细胞增多症中肥大细胞异常增殖的几个其他信号分子。这些进展使我们更好地了解了晚期系统性肥大细胞增多症的生物学特性，并开发了新的靶向治疗概念。在此，我们回顾了晚期系统性肥大细胞增多症的生物学和发病机制，特别关注新的分子发现以及当前和不断发展的治疗选择。
