Cancer Research UK Children's Cancer Group, Manchester Academic Health Science Centre, School of Cancer & Enabling Sciences, University of Manchester, Manchester, United Kingdom.
Blood. 2011 Jul 21;118(3):638-49. doi: 10.1182/blood-2010-09-307330. Epub 2011 May 23.
We developed a murine model of CNS disease to obtain a better understanding of the pathogenesis of CNS involvement in pre-B-cell acute lymphoblastic leukemia (ALL). Semiquantitative proteomic discovery-based approaches identified unique expression of asparaginyl endopeptidase (AEP), intercellular adhesion molecule 1 (ICAM1), and ras-related C3 botulinum toxin substrate 2 (RAC2), among others, in an invasive pre-B-cell line that produced CNS leukemia in NOD-SCID mice. Targeting RAC2 significantly inhibited in vitro invasion and delayed disease onset in mice. Induced expression of RAC2 in cell lines with low/absent expression of AEP and ICAM1 did not result in an invasive phenotype or murine CNS disease. Flow cytometric analysis identified an enriched population of blast cells expressing ICAM1/lymphocyte function associated antigen-1 (LFA-1)/CD70 in the CD10(+)/CD19(+) fraction of bone marrow aspirates obtained from relapsed compared with normal controls and those with primary disease. CD10(+)/CD19(+) fractions obtained from relapsed patients also express RAC2 and give rise to CNS disease in mice. Our data suggest that combinations of processes are involved in the pathogenesis of CNS disease in pre-B-cell ALL, support a model in which CNS disease occurs as a result of external invasion, and suggest that targeting the processes of adhesion and invasion unique to pre-B cells may prevent recurrences within the CNS.
我们建立了中枢神经系统疾病的小鼠模型，以更好地了解前 B 细胞急性淋巴细胞白血病（ALL）中枢神经系统受累的发病机制。基于半定量蛋白质组学发现的方法鉴定出，在一种具有侵袭性的前 B 细胞系中，独特表达天冬酰胺内肽酶（AEP）、细胞间黏附分子 1（ICAM1）和 Ras 相关 C3 肉毒杆菌毒素底物 2（RAC2）等，该细胞系可在 NOD-SCID 小鼠中产生中枢神经系统白血病。靶向 RAC2 可显著抑制体外侵袭，并延迟小鼠疾病的发生。在 AEP 和 ICAM1 低表达/无表达的细胞系中诱导 RAC2 的表达，不会导致侵袭表型或小鼠中枢神经系统疾病。流式细胞术分析鉴定出，与正常对照和初发病例相比，复发患者骨髓抽吸物中 CD10(+)/CD19(+) 部分的 CD10(+)/CD19(+) 细胞群中表达 ICAM1/淋巴细胞功能相关抗原 1（LFA-1）/CD70 的 blast 细胞丰富。从复发患者获得的 CD10(+)/CD19(+) 部分也表达 RAC2，并在小鼠中引发中枢神经系统疾病。我们的数据表明，前 B 细胞 ALL 中枢神经系统疾病的发病机制涉及多种过程，支持中枢神经系统疾病是由于外部侵袭引起的模型，并表明靶向前 B 细胞特有的黏附和侵袭过程可能防止中枢神经系统内的复发。
