Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas.
Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas.
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鉴定 TRA-1-60 阳性细胞为滤泡性淋巴瘤中有效的难治性细胞群。
DOI：
10.1111/cas.13870
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Kondo E.
中科院分区：
文献类型：
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作者：
Takata K;Saito K;Maruyama S;Miyata-Takata T;Iioka H;Okuda S;Ling Y;Karube K;Miki Y;Maeda Y;Yoshino T;Steidl C;Kondo E.
尽管接受利妥昔单抗联合化疗，滤泡性淋巴瘤（FL）患者经常遭受肿瘤复发，并了解FL复发的原因将因此显着改善肿瘤治疗。在本研究中，我们表明TRA-1 - 60-表达细胞是FL中的独特群体，与传统干细胞标志物Oct 3/4和ALDH 1-阳性群体趋同，并抵抗当前的B-淋巴瘤药物。仅在FL组织中的散在淋巴瘤细胞以及生殖中心内的静息B-淋巴细胞中观察到TRA-1 - 60表达。复发和同源原发组织之间的回顾性比较显示，来自利妥昔单抗、环磷酰胺、羟基柔红霉素、长春新碱和泼尼松（R-CHOP）处理的FL的TRA-1 - 60阳性细胞数量相对于原发组织增加，这一发现得到了不同利妥昔单抗处理的FL细胞系FL-18和DOHH 2的测定的证实，其中TRA阳性细胞数量与未处理的样品相比增加了10倍以上。一致的是，少量TRA-1 - 60-阳性FL-18细胞皮下植入与TRA阴性细胞异种移植的肿瘤相比，小鼠体内肿瘤体积大12倍（P= 0.0021 < 0.005），重量重13倍（P= 0.0015 < 0.005）。为了解释这些结果，基因表达谱和qPCR分析表明TRA-1 - 60-阳性细胞定义了与TRA-阴性细胞不同的群体，具有多种药物转运蛋白和治疗抗性基因的上调。因此，FL中的TRA-1 - 60-表达细胞被认为对常规治疗药物非常难治，这可能解释了其难治性复发。
Despite receiving rituximab‐combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA‐1‐60‐expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1‐positive population, and resist current B‐lymphoma agents. TRA‐1‐60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B‐lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA‐1‐60‐positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R‐CHOP)‐treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab‐treated FL cell lines, FL‐18 and DOHH2, wherein TRA‐positive cell numbers increased over 10‐fold compared to the untreated sample. Concordantly, scanty TRA‐1‐60‐positive FL‐18 cells implanted s.c. into mice evinced potent tumor‐initiating capacity in vivo, where tumors were 12‐fold larger in volume (P= 0.0021 < 0.005) and 13‐fold heavier in weight (P= 0.0015 < 0.005) compared to those xenografted from TRA‐negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA‐1‐60‐positive cells defined a distinct population from that of TRA‐negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA‐1‐60‐expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.