Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function.
Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function.
复制标题
急性淋巴细胞白血病骨髓微环境中的异常Notch信号传导抑制成骨细胞介导的造血生态位功能支持。
DOI：
10.1158/0008-5472.can-15-2092
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发表时间：
2016
期刊：
影响因子：
11.2
通讯作者：
Zhou,Lan
中科院分区：
文献类型：
--
作者：
Wang,Weihuan;Zimmerman,Grant;Huang,Xiaoran;Yu,Shuiliang;Myers,Jay;Wang,Yiwei;Moreton,Stephen;Nthale,Joseph;Awadallah,Amad;Beck,Rose;Xin,Wei;Wald,David;Huang,AlexY;Zhou,Lan
超过一半的T细胞急性淋巴细胞白血病(T-ALL)患者在Notch1的细胞内区域存在功能获得突变。T-ALL和复发性B细胞急性淋巴细胞白血病患者常发生骨髓弥漫性浸润，预后较差。然而，白血病在骨髓中生长的机制以及由此产生的对造血的生物学影响尚不清楚。在这里，我们使用T-ALL小鼠模型和人类T-ALL异种移植模型，研究了白血病骨髓基质中导致正常造血抑制的靶向性细胞和分子异常。我们发现活跃的白血病细胞增殖抑制了正常的造血干细胞和祖细胞(HSPC)的增殖和归巢到血管周围区域。此外，白血病的发展伴随着骨膜衬里成骨细胞群的抑制。我们进一步证明，基质中异常的Notch激活在负性调节成骨细胞上CXLC12的表达及其分化中起着重要作用。缺口阻断逆转了HSPC周期减弱、白血病相关的异常血系分布、血小板减少以及成骨细胞和HSPC丰度的恢复，改善了成骨细胞的造血支持功能。最后，我们证实成骨细胞频率降低和Notch信号增强也是人类所有组织的骨髓基质的特征。总而言之，我们的发现表明，以白血病浸润性造血细胞利基为靶点的治疗可能恢复HSPC的动态平衡并改善所有患者的预后。©2016 AACR。
More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain ofNotch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients.Cancer Res; 76(6); 1641–52. ©2016 AACR.