Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Comprehensive Cancer Center, Spitalgasse 23, 1090 Vienna, Austria.
Int J Mol Sci. 2019 Nov 20;20(23):5826. doi: 10.3390/ijms20235826.
The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML.
降钙素基因相关肽（CGRP）通过 G 蛋白偶联受体（CALCRL）及其辅助受体（RAMP1）发挥作用，在偏头痛中发挥关键作用，这导致了几种抑制化合物的临床开发。最近，高表达与急性髓系白血病（AML）的不良预后相关。因此，我们研究了 CGRP-CALCRL 轴在 AML 中的功能作用。为此，我们使用了分析、人 AML 细胞系、原发性患者样本和基于 C57BL/6 的 AML 小鼠模型。我们发现，在 AML 复发时、白血病干细胞（LSCs）与白血病细胞相比，以及在 LSCs 与正常造血干细胞相比，上调。CGRP 可保护受体阳性 AML 细胞系和原发性 AML 样本免受 AML 治疗中使用的细胞毒性药物诱导的细胞凋亡，而这种作用可被特异性拮抗剂抑制。此外，CGRP 拮抗剂 olcegepant 可增加分化并减少 AML 小鼠模型中的白血病负担以及关键干细胞特性。这些数据为进一步研究 CGRP-CALCRL 抑制在 AML 治疗中的可能作用提供了依据。
