Rigolin Gian Matteo, Saccenti Elena, Rizzotto Lara, Ferracin Manuela, Martinelli Sara, Formigaro Luca, Cibien Francesca, Cavallari Maurizio, Lista Enrico, Daghia Giulia, Sofritti Olga, Ciccone Maria, Cavazzini Francesco, Lupini Laura, Bassi Cristian, Zagatti Barbara, Negrini Massimo, Cuneo Antonio
Hematology Section, Department of Medical Sciences, University of Ferrara, University Hospital Arcispedale S. Anna, Ferrara, Italy.
Oncotarget. 2014 Jan 15;5(1):140-9. doi: 10.18632/oncotarget.1382.
The majority of patients with chronic lymphocytic leukemia (CLL) and favorable prognostic features live for long periods without treatment. However, unexpected disease progression is observed in some cases. In a cohort of untreated CD38- CLL patients with normal FISH or isolated 13q- we found that, by fluorescence in situ hybridization (FISH), 16/28 cases presented, within immunomagnetic sorted CD38+ cells, genetic lesions undetectable in the CD38- fraction. These patients showed a shorter time to first treatment (TTFT, p=0.0162) in comparison to cases without FISH lesions in CD38+ cells. Patients with FISH abnormalities in CD38+ cells showed a distinctive microRNA profile, characterized by the down-regulation of miR-125a-5p both in the CD38- and CD38+ populations. In an independent cohort of 71 consecutive untreated CD38- CLL with normal FISH or isolated 13q-, a lower miR125a-5p expression was associated with a shorter TTFT both in univariate and multivariate analysis (p=0.003 and 0.016, respectively) and with a higher prevalence of mutations (7/12 vs 0/8, p=0.015) as assessed by next-generation sequencing. In conclusion, our data showed previously unrecognized subclonal heterogeneity within the CD38+ fraction of CD38- CLL patients with low-risk FISH findings and suggested an association between down-regulated miR-125a-5p expression, genetic complexity and worse outcome.
大多数具有良好预后特征的慢性淋巴细胞白血病（CLL）患者未经治疗可长期存活。然而，在某些情况下会观察到意想不到的疾病进展。在一组FISH结果正常或仅存在13q-缺失的未经治疗的CD38- CLL患者中，我们发现，通过荧光原位杂交（FISH）检测，在免疫磁珠分选的CD38+细胞中，16/28例出现了在CD38-细胞组分中未检测到的基因损伤。与CD38+细胞中无FISH损伤的病例相比，这些患者首次治疗时间（TTFT）更短（p = 0.0162）。CD38+细胞中存在FISH异常的患者表现出独特的微小RNA谱，其特征是在CD38-和CD38+细胞群体中miR-125a-5p均下调。在另一组连续71例FISH结果正常或仅存在13q-缺失的未经治疗的CD38- CLL患者中，单因素和多因素分析均显示，较低的miR125a-5p表达与较短的TTFT相关（分别为p = 0.003和0.016），并且与通过二代测序评估的更高的突变发生率相关（7/12 vs 0/8，p = 0.015）。总之，我们的数据显示，在具有低风险FISH结果的CD38- CLL患者的CD38+细胞组分中存在此前未被认识到的亚克隆异质性，并提示miR-125a-5p表达下调、基因复杂性与较差预后之间存在关联。
