Department of Medical and Surgical Critical Care, Section of Hematology, University of Florence, Italy.
Blood. 2011 Nov 10;118(19):5227-34. doi: 10.1182/blood-2011-06-363424. Epub 2011 Sep 14.
We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.
我们对 370 例原发性骨髓纤维化（PMF）和 148 例真性红细胞增多症后/原发性血小板增多症后骨髓纤维化（PPV/PET-MF）患者进行了 EZH2 基因突变分析。诊断时的突变状态与血液学参数、临床表现和预后相关。在 5.9%的 PMF、1.2%的 PPV-MF 和 9.4%的 PET-MF 患者中检测到 25 种不同的 EZH2 突变；大多数为外显子杂合错义改变。在 29 例可评估患者中，12 例（41.4%）和 6 例（22.2%）同时存在 EZH2 突变和 JAK2V617F 或 ASXL1 突变；2 例和 1 例患者分别发现 TET2 和 CBL 突变。EZH2 突变的 PMF 患者在诊断时白细胞计数、原始细胞计数和脾脏较大，其中大多数（52.6%）处于高风险国际预后评分系统（IPSS）类别。中位随访 39 个月后，128 例患者（25.9%）死亡，81 例（63.3%）死于白血病。EZH2 突变的 PMF 患者白血病无进展生存（LFS）和总生存（OS）显著降低（P=0.028 和 P<0.001）；而在 PPV/PET-MF 患者中则无此影响，可能是由于突变病例较少。多变量分析显示，PMF 患者的生存由高危 IPSS 类别、JAK2V617F 等位基因负担<25%和 EZH2 突变状态预测。综上所述，EZH2 突变与 PMF 患者的生存时间缩短独立相关。
