Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells.,Oncogenesis

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Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells.
Oncogenesis ( IF 5.9 ) Pub Date : 2019-05-10 , DOI: 10.1038/s41389-019-0142-2
Katie B Holmes ₁ , Ildar I Sadreev _{1,

2} , Andy C Rawstron ₃ , Tal Munir ₃ , David R Westhead ₂ , Peter Hillmen ₁ , Pascal F Lefevre ₁

Affiliation

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries. It has recently been shown that the homogeneity of the chromatin landscape between CLL cells contrasts with the important observed genetic heterogeneity of the disease. To gain further insight into the consequences of disease evolution on the epigenome's plasticity, we monitored changes in chromatin structure occurring in vivo in CLL cells from patients receiving continuous Ibrutinib treatment. Ibrutinib, an oral inhibitor of the Bruton's tyrosine kinase (BTK) has proved to be remarkably efficient against treatment naïve (TN), heavily pre-treated and high-risk chronic lymphocytic leukaemia (CLL), with limited adverse events. We established that the chromatin landscape is significantly and globally affected in response to Ibrutinib. However, we observed that prior to treatment, CLL cells show qualitative and quantitative variations in chromatin structure correlated with both EZH2 protein level and cellular response to external stimuli. Then, under prolonged exposure to Ibrutinib, a loss of the two marks associated with lysine 27 (acetylation and trimethylation) was observed. Altogether, these data indicate that the epigenome of CLL cells from the peripheral blood change dynamically in response to stimuli and suggest that these cells might adapt to the Ibrutinib "hit" in a process leading toward a possible reduced sensitivity to treatment.

中文翻译：

依鲁替尼诱导慢性淋巴细胞白血病细胞的染色质重组。

慢性淋巴细胞性白血病（CLL）是西方国家最常见的白血病。最近显示，CLL细胞之间染色质分布的同质性与该疾病重要的观察到的遗传异质性形成对比。为了进一步了解疾病演变对表观基因组可塑性的影响，我们监测了接受连续依鲁替尼治疗的患者的CLL细胞体内染色质结构的变化。事实证明，依鲁替尼是一种布鲁顿酪氨酸激酶（BTK）的口服抑制剂，对初治（TN），重度治疗和高风险的慢性淋巴细胞性白血病（CLL）具有显着的疗效，且不良反应有限。我们确定，依鲁替尼对染色质的影响显着且在全球范围内受到影响。然而，我们观察到，在治疗之前，CLL细胞在染色质结构上显示出定性和定量变化，与EZH2蛋白水平和细胞对外部刺激的反应相关。然后，在长期暴露于依鲁替尼的情况下，观察到与赖氨酸27相关的两个标记（乙酰化和三甲基化）的丧失。总而言之，这些数据表明来自外周血的CLL细胞的表观基因组响应于刺激而动态变化，并暗示这些细胞可能在可能导致对治疗的敏感性降低的过程中适应依鲁替尼的“打击”。观察到与赖氨酸27有关的两个标记（乙酰化和三甲基化）的丧失。总而言之，这些数据表明来自外周血的CLL细胞的表观基因组响应于刺激而动态变化，并暗示这些细胞可能在可能导致对治疗的敏感性降低的过程中适应依鲁替尼的“打击”。观察到与赖氨酸27有关的两个标记（乙酰化和三甲基化）的丧失。总而言之，这些数据表明来自外周血的CLL细胞的表观基因组响应于刺激而动态变化，并暗示这些细胞可能在可能导致对治疗的敏感性降低的过程中适应依鲁替尼的“打击”。

更新日期：2019-11-18

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