IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F.
IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F.
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异柠檬酸脱氢酶（IDH）突变在急变期骨髓增生性肿瘤中很常见，因此可能导致白血病转化。我们在301例慢性期原发性骨髓纤维化（PMF）患者中研究了这种可能性。12例患者（4%）检测到突变型IDH：7例IDH 2（5例R140 Q，1例R140 W和1例R172 G）和5例IDH 1（3例R132 S和2例R132 C）。总之，12名IDH突变患者中有6名（50%）也表达JAK 2 V617 F。总体而言，18例（6%）患者仅显示MPL突变，164例（54.3%）仅显示JAK 2突变。多变量分析，占传统的危险因素揭示了较差的总生存期（OS; P=0.03）和无白血病生存期（LFS; P=0.003）IDH突变患者：无JAK 2或MPL突变患者的OS风险比（HR）分别为0.39（95%置信区间（95% CI）0.2-0.75）、0.50（95% CI 0.27-0.95）和0.53（95% CI 0.23-1.2）。进一步的分析揭示了在存在（分别为P=0.0002和P<0.0001）的情况下突变体IDH对OS和LFS的更显著的作用，这与不存在（P=0.34和P=0.64）伴随的JAK 2 V617 F相反。在慢性期和急变期疾病期间获得的配对样本的分析揭示了IDH和JAK 2突变在两个时间点的存在。我们的观察表明，PMF中的IDH突变是白血病转化的独立预测因子，并提高了与JAK 2 V617 F协同致白血病的可能性。
Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2–0.75), 0.50 (95% CI 0.27–0.95) and 0.53 (95% CI 0.23–1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F.
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