美國研究人員最新研究發(fā)現(xiàn),，白血病細(xì)胞把人體骨髓當(dāng)成“避風(fēng)港”，它們能在其中棲身并汲取養(yǎng)分,。研究人員稱,，借助這一發(fā)現(xiàn)有望開發(fā)出更有針對性的白血病化療方法。
白血病患者在化療期間首選服用的是天冬酰胺酶抗癌藥物,。天冬酰胺酶會(huì)耗盡患者體內(nèi)白血病細(xì)胞所需的天冬酰胺,，從而導(dǎo)致白血病細(xì)胞死亡，而正常細(xì)胞不會(huì)受太大影響,。
美國圣祖德兒童研究醫(yī)院達(dá)里奧·坎帕納領(lǐng)導(dǎo)的研究小組在最新一期美國《臨床檢查雜志》上報(bào)告說,，他們在試驗(yàn)中發(fā)現(xiàn)，白血病細(xì)胞會(huì)潛藏到人體骨髓間充質(zhì)細(xì)胞中,。骨髓間充質(zhì)細(xì)胞會(huì)釋放大量天冬酰胺分子,，供白血病細(xì)胞使用，相當(dāng)于為白血病細(xì)胞提供了一個(gè)保護(hù)性的小環(huán)境,，使白血病細(xì)胞再次活躍起來,。
天冬酰胺這種氨基酸對于白血病細(xì)胞來說,，是保證正常存活的一種非常關(guān)鍵的養(yǎng)分，但白血病細(xì)胞本身不能高效地合成天冬酰胺,，而需要利用人體內(nèi)的天冬酰胺,。研究人員說，一些患有急性淋巴細(xì)胞白血病的兒童服用天冬酰胺酶藥物后病情仍出現(xiàn)反復(fù),，就是因?yàn)轶w內(nèi)骨髓間充質(zhì)細(xì)胞釋放出的天冬酰胺抵消了藥效,。
坎帕納介紹說，他們進(jìn)一步研究發(fā)現(xiàn),，骨髓間充質(zhì)細(xì)胞中有一種名為ＡＳＮＳ的基因,，對骨髓間充質(zhì)細(xì)胞能否釋放大量天冬酰胺分子起關(guān)鍵作用。研究人員希望借此找到一種方法,，破壞白血病細(xì)胞的“避風(fēng)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: [email protected] .
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.
