Leukemia-derived exosomes and cytokines pave the way for entry into the brain
Leukemia-derived exosomes and cytokines pave the way for entry into the brain
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DOI：
10.1002/jlb.3a0218-054r
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发表时间：
2019-04-01
影响因子：
5.5
通讯作者：
Wilson, Bridget S.
中科院分区：
文献类型：
--
作者：
Kinjyo, Ichiko;Bragin, Denis;Wilson, Bridget S.
急性淋巴细胞白血病（ALL）原始细胞浸润中枢神经系统仍然是一个主要的临床问题，具有化疗耐药性复发和治疗相关发病率的高风险。尽管中枢神经系统预防治疗通常包含在治疗方案中，但在了解介导白血病细胞进入中枢神经系统的机制以及大脑中常驻细胞的作用方面仍存在显着差距。在这项研究中，我们在免疫功能低下的小鼠中采用了人类 B 细胞前体 (BCP)-ALL 的异种移植模型。该模型系统概括了患者软脑膜受累的关键病理特征，并为涉及脑实质侵犯的罕见病例提供了见解。我们检查了移植的白血病原始细胞对受体小鼠大脑的浸润情况，并提供了证据表明原始细胞和大脑驻留细胞之间的相互作用导致大脑微环境中宿主细胞的异常激活。 BCP-ALL 母细胞还释放多种细胞因子和含有 IL-15 的外泌体，它们与星形胶质细胞和脑血管内皮细胞结合并被星形胶质细胞和脑血管内皮细胞内化。白血病侵袭与星形胶质细胞产生 VEGF-AA 和血脑屏障 (BBB) 完整性破坏有关。 NALM6 细胞系中 IL-15 或 IL-15R α 的敲低可减少移植小鼠的中枢神经系统浸润。这些结果为淋巴母细胞调节大脑微环境以突破血脑屏障进行转移侵袭的多种机制提供了重要的见解。
Infiltration of acute lymphoblastic leukemia (ALL) blasts into the CNS remains as a major clinical problem, with high risk for chemotherapy-resistant relapse and treatment-related morbidity. Despite the common inclusion of CNS prophylaxis treatments in therapy regimens, there are significant gaps in understanding the mechanisms that mediate leukemia cell entry into the CNS as well as roles for resident cells in the brain. In this study, we employ a xenograft model of human B cell precursor (BCP)-ALL in immunocompromised mice. This model system recapitulates key pathological characteristics of leptomeningeal involvement seen in patients and provides insights into rare cases that involve parenchymal invasion. We examine the infiltration of engrafted leukemia blasts into brains of recipient mice and provide evidence that the interaction between blasts and brain resident cells causes aberrant activation of host cells in the brain microenvironment. BCP-ALL blasts also release multiple cytokines and exosomes containing IL-15 that bind and are internalized by astrocytes and brain vessel endothelial cells. Leukemic invasion is linked to production of VEGF-AA by astrocytes and disruption of the blood-brain-barrier (BBB) integrity. Knockdown of either IL-15 or IL-15R alpha in the NALM6 cell line decreases CNS infiltration in engrafted mice. These results provide important insights into the multiple mechanisms by which lymphoblasts modulate the brain microenvironment to breach the BBB for metastatic invasion.