美国研究人员最新研究发现，白血病细胞把人体骨髓当成“避风港”，它们能在其中栖身并汲取养分。研究人员称，借助这一发现有望开发出更有针对性的白血病化疗方法。
白血病患者在化疗期间首选服用的是天冬酰胺酶抗癌药物。天冬酰胺酶会耗尽患者体内白血病细胞所需的天冬酰胺，从而导致白血病细胞死亡，而正常细胞不会受太大影响。
美国圣祖德儿童研究医院达里奥·坎帕纳领导的研究小组在最新一期美国《临床检查杂志》上报告说，他们在试验中发现，白血病细胞会潜藏到人体骨髓间充质细胞中。骨髓间充质细胞会释放大量天冬酰胺分子，供白血病细胞使用，相当于为白血病细胞提供了一个保护性的小环境，使白血病细胞再次活跃起来。
天冬酰胺这种氨基酸对于白血病细胞来说，是保证正常存活的一种非常关键的养分，但白血病细胞本身不能高效地合成天冬酰胺，而需要利用人体内的天冬酰胺。研究人员说，一些患有急性淋巴细胞白血病的儿童服用天冬酰胺酶药物后病情仍出现反复，就是因为体内骨髓间充质细胞释放出的天冬酰胺抵消了药效。
坎帕纳介绍说，他们进一步研究发现，骨髓间充质细胞中有一种名为ＡＳＮＳ的基因，对骨髓间充质细胞能否释放大量天冬酰胺分子起关键作用。研究人员希望借此找到一种方法，破坏白血病细胞的“避风港”。
部分英文原文：
Published Online March 22, 2007
J. Clin. Invest. doi:10.1172/JCI30235.
Online First Publication
Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase
Shotaro Iwamoto1, Keichiro Mihara1, James R. Downing2,3, Ching-Hon Pui1,2,3 and Dario Campana1,2,3
1Department of Oncology and 2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. 3University of Tennessee College of Medicine, Memphis, Tennessee, USA.
Address correspondence to: Dario Campana, Department of Oncology, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA. Phone: (901) 495-2528; Fax: (901) 495-5947; E-mail: dario.campana@stjude.org .
Received for publication September 4, 2006, and accepted in revised form January 30, 2007.
Because of their low asparagine synthetase (ASNS) expression and asparagine biosynthesis, acute lymphoblastic leukemia (ALL) cells are exquisitely sensitive to asparagine depletion. Consequently, asparaginase is a major component of ALL therapy, but the mechanisms regulating the susceptibility of leukemic cells to this agent are unclear. In 288 children with ALL, cellular ASNS expression was more likely to be high in T-lineage ALL and low in B-lineage ALL with TEL-AML1 or hyperdiploidy. However, ASNS expression levels in bone marrow–derived mesenchymal cells (MSCs), which form the microenvironment where leukemic cells grow, were on average 20 times higher than those in ALL cells. MSCs protected ALL cells from asparaginase cytotoxicity in coculture experiments. This protective effect correlated with levels of ASNS expression: downregulation by RNA interference decreased the capacity of MSCs to protect ALL cells from asparaginase, whereas enforced ASNS expression conferred enhanced protection. Asparagine secretion by MSCs was directly related to their ASNS expression levels, suggesting a mechanism — increased concentrations of asparagine in the leukemic cell microenvironment — for the protective effects we observed. These results provide what we believe to be a new basis for understanding asparaginase resistance in ALL and indicate that MSC niches in the bone marrow can form a safe haven for leukemic cells.
