Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia
Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia
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DOI：
10.1182/bloodadvances.2017004960
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发表时间：
2017-09-01
期刊：
影响因子：
7.5
通讯作者：
Pflumio, Francoise
中科院分区：
文献类型：
--
作者：
Cahu, Xavier;Calvo, Julien;Pflumio, Francoise
t细胞急性淋巴细胞白血病（T-ALL）在身体的各个骨骨髓（BM）部位扩张。我们使用体内动物模型研究了不同的脑转移位点是否可以不同地调节T-ALL的繁殖。我们观察到小鼠和人的T-ALL在尾椎基底膜中发育较胸椎基底膜慢。从尾部BM中恢复的T-ALL显示出较低的细胞表面标志物表达，代谢和细胞周期进展减慢，显示出休眠表型。在功能上，尾源性T-ALL表现出短期体外生长缺陷和体内繁殖延迟。这些特征是非细胞自主的，因为来自尾部和胸部的T-ALL具有相同的基因组异常，功能差异在体内和长时间的体外分析中消失。重要的是，尾部衍生的T-ALL对细胞周期相关药物（如硫酸长春新碱和阿糖胞苷）表现出更高的内在抗性。值得注意的是，从性腺脂肪组织或与脂肪细胞共培养中恢复的T-ALL具有相同的代谢、细胞周期、表型或化学耐药特征，尾部衍生的T-ALL表明脂肪细胞可能参与了T-ALL的尾部BM印记。综上所述，这些结果表明，脑转移位点不同地协调T-ALL的传播，为白血病细胞提供了特定的特征，如静止和对细胞周期依赖性化疗的反应降低。
T-cell acute lymphoblastic leukemia (T-ALL) expands in various bonemarrow (BM) sites of the body. We investigated whether different BM sites could differently modulate T-ALL propagation using in vivo animal models. We observed that mouse and human T-ALL develop slowly in the BM of tail vertebrae compared with the BM from thorax vertebrae. T-ALL recovered from tail BM displays lower cell-surfacemarker expression and decreased metabolism and cell-cycle progression, demonstrating a dormancy phenotype. Functionally, tailderived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are noncell-autonomous because T-ALL fromtail and thorax shares identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL displays higher intrinsic resistance to cell-cycle-related drugs (ie, vincristine sulfate and cytarabine). Of note, T-ALL recovered from gonadal adipose tissues or from cocultures with adipocytes shares metabolic, cell-cycle, and phenotypic or chemoresistance features, with tail-derived T-ALL suggesting adipocytes may participate in the tail BM imprints on T-ALL. Altogether these results demonstrate that BM sites differentially orchestrate T-ALL propagation stamping specific features to leukemic cells such as quiescence and decreased response to cell-cycle-dependent chemotherapy.