Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.
Munich Leukemia Laboratory, Munich, Germany.
Leukemia. 2015 May;29(5):1115-22. doi: 10.1038/leu.2015.4. Epub 2015 Jan 8.
To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte-macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V(+) indolent SM (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1-4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V(+) single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0-95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V(-). These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD,
为了探究系统性肥大细胞增多症（SM）的分子特征及其预后意义，我们分析了 KIT D816V（+）惰性 SM（ISM，n=4）、冒烟型 SM（SSM，n=2）、侵袭性 SM（ASM，n=1）、伴克隆性血液非肥大细胞谱系疾病的 SM（SM-AHNMD，n=5）和伴克隆性血液非肥大细胞谱系疾病的侵袭性 SM（ASM-AHNMD，n=7）患者的粒细胞-巨噬细胞集落形成祖细胞（CFU-GM）突变状态。所有（A）SM-AHNMD 患者（n=12）在 11 个检测基因中均携带 1-4 个（中位数 3 个）额外突变，最常见的是 TET2、SRSF2、ASXL1、CBL 和 EZH2。在多突变（A）SM-AHNMD 中，在 12 例患者中的 8 例（中位数 60%，范围 0-95%）中鉴定出 KIT D816V（+）单细胞衍生 CFU-GM 集落。在所有患者中均鉴定出 CFU-GM 集落中的额外突变，逻辑层次分析表明 TET2、SRSF2 和 ASXL1 的突变先于 KIT D816V。在 ISM/SSM 中未检测到额外突变，并且 CFU-GM 集落均为 KIT D816V（-）。这些数据表明：（a）（A）SM-AHNMD 是一种多突变肿瘤；（b）在 ASM-AHNMD 中，TET2、SRSF2 或 ASXL1 的突变先于 KIT D816V。
