Medical School, Sigmund Freud University, Vienna, Austria.
Department of Internal Medicine V with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, Vienna, Austria.
Eur J Haematol. 2022 Jul;109(1):50-57. doi: 10.1111/ejh.13768. Epub 2022 Mar 23.
A multistep pathogenesis of myeloid leukemia including mutations in epigenetic, spliceosome, and signaling genes has been recently demonstrated in a preclinical model but is poorly validated in patients.
Clinical, phenotypic, and biologic features were compared between three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14).
Median survival was 90, 45, and 9 months, respectively (p = .001). Whereas no patient in the T and TS group transformed into acute myeloid leukemia (AML), 6/14 patients in the TSN group had AML at study entry or transformed during follow-up. Leukocyte counts, blast cell counts, and LDH levels were significantly higher in TSN vs. TS and T, respectively, whereas hemoglobin and platelet values were not significantly different. Increased growth factor-independent myeloid colony formation was restricted to TSN but not found in T and TS, respectively. The proportion of patients showing in vitro myelomonocytic skewing in T, TS, and TSN was 0%, 56%, and 100%, respectively (p = .010).
Our results demonstrate that the model of multistep pathogenesis in CMML can be recapitulated in patients regarding clinical, phenotypic, and biologic features.
最近在临床前模型中证实了骨髓增生异常综合征（myeloid leukemia）的多步骤发病机制，包括表观遗传、剪接体和信号基因的突变，但在患者中验证不足。
比较了三个不同分子定义的 CMML 队列的临床、表型和生物学特征，包括 TET2 单突变患者（T，n=10）、TET2/SRSF2 双突变患者（TS，n=19）和除 TET2/SRSF2 共突变外还具有 NRAS 突变的患者（TSN，n=14）。
中位生存时间分别为 90、45 和 9 个月（p=0.001）。尽管 T 和 TS 组中没有患者转化为急性髓系白血病（AML），但 TSN 组中有 6/14 患者在研究入组时或随访期间转化为 AML。与 TS 和 T 相比，TSN 组的白细胞计数、原始细胞计数和 LDH 水平显著升高，而血红蛋白和血小板值无显著差异。独立于生长因子的髓样集落形成增加仅见于 TSN，而不在 T 和 TS 中发现。分别在 T、TS 和 TSN 中观察到体外髓单核细胞偏斜的患者比例为 0%、56%和 100%（p=0.010）。
我们的结果表明，CMML 中多步骤发病机制的模型可以在患者中重现，包括临床、表型和生物学特征。
