Elaskalani Omar, Gilmore Grace, Hagger Madison, Baker Ross I, Metharom Pat
Telethon Kids Institute, Cancer Centre, Nedlands, WA 6009, Australia.
Centre for Child Health Research, University of Western Australia, Crawley, WA 6009, Australia.
Cancers (Basel). 2022 Nov 23;14(23):5750. doi: 10.3390/cancers14235750.
Chronic lymphocytic leukemia patients have an increased bleeding risk with the introduction of Bruton tyrosine kinase (BTK) inhibitors. BTK is a signaling effector downstream of the platelet GPVI receptor. Innate platelet dysfunction in CLL patients and the contribution of the leukemia microenvironment to the anti-platelet effect of BTK inhibitors are still not well defined. Herein, we investigated platelet function in stable, untreated CLL patients in comparison to age-matched healthy subjects as control. Secondly, we proposed a novel mechanism of platelet dysfunction via the adenosinergic pathway during BTK inhibitor therapy. Our data indicate that the nucleotidase that produces adenosine, CD73, was expressed on one-third of B-cells in CLL patients. Inhibition of CD73 improved platelet response to ADP in the blood of CLL patients ex vivo. Using healthy platelets, we show that adenosine 2A (A2A) receptor activation amplifies the anti-platelet effect of ibrutinib (10 nM). Ibrutinib plus an A2A agonist-but not ibrutinib as a single agent-significantly inhibited collagen (10 µg/mL)-induced platelet aggregation. Mechanistically, A2A activation attenuated collagen-mediated inhibition of p-VASP and synergized with ibrutinib to inhibit the phosphorylation of AKT, ERK and SYK kinases. This manuscript highlights the potential role of adenosine generated by the microenvironment in ibrutinib-associated bleeding in CLL patients.
慢性淋巴细胞白血病患者在使用布鲁顿酪氨酸激酶（BTK）抑制剂后出血风险增加。BTK是血小板糖蛋白VI受体下游的信号效应器。慢性淋巴细胞白血病患者先天性血小板功能障碍以及白血病微环境对BTK抑制剂抗血小板作用的影响仍未完全明确。在此，我们研究了稳定的未经治疗的慢性淋巴细胞白血病患者与年龄匹配的健康对照者的血小板功能。其次，我们提出了一种在BTK抑制剂治疗期间通过腺苷能途径导致血小板功能障碍的新机制。我们的数据表明，产生腺苷的核苷酸酶CD73在三分之一的慢性淋巴细胞白血病患者B细胞上表达。抑制CD73可改善慢性淋巴细胞白血病患者血液中血小板对ADP的反应性。使用健康血小板，我们发现腺苷2A（A2A）受体激活可增强依鲁替尼（10 nM）的抗血小板作用。依鲁替尼加A2A激动剂——而不是单独使用依鲁替尼——可显著抑制胶原蛋白（10 µg/mL）诱导的血小板聚集。从机制上讲，A2A激活减弱了胶原蛋白介导的对p-VASP的抑制作用，并与依鲁替尼协同抑制AKT、ERK和SYK激酶的磷酸化。本论文强调了微环境产生的腺苷在慢性淋巴细胞白血病患者依鲁替尼相关出血中的潜在作用。
