PNAS：日本发现治疗白血病的关键蛋白

生物谷

    生物谷报道：美国《国家科学院学报》（PNAS）日前公布的一项研究报告说，日本研究人员发现了代号为CD96的蛋白，可作为识别导致最常见的成人急性白血病的恶性干细胞活动的标志，从而在寻求根治白血病的方法上迈出关键一步。

    报告说，急性成髓细胞性白血病（AML）是血液和骨髓的癌症，因单独使用药物常常无法达到根治的目的，所以通常采用多种药物治疗。白血病干细胞能够隐藏在体内并不断分裂，导致癌症在治疗后复发。

    日本研究人员发现了白血病干细胞表面代号为CD96的蛋白，可作为识别这些活动的干细胞的标志。正常血液干细胞通常不带这个标志。为验证他们的理论，研究人员分别将含有CD96蛋白和不含CD96蛋白的急性成髓细胞性白血病细胞的样本植入老鼠体内。结果研究人员发现，只有含有CD96蛋白的细胞开始复制生长，由此表明CD96蛋白的确是白血病干细胞活动的标志。

    研究报告的主要作者、大阪大学医学研究生院的研究员保仙直树说，此项研究迈出了第一步。但研究人员能否找到有效的抗体疗法，让白血病患者自身识别并杀死癌细胞，有待进一步研究。（引自新华网）

原始出处:

Published online before print June 18, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0704271104

CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia

( hematopoietic stem cell )

Naoki Hosen * ${dagger}$ ${ddagger}$ , Christopher Y. Park *, Naoya Tatsumi ${sect}$ , Yusuke Oji ${sect}$ , Haruo Sugiyama ${sect}$ , Martin Gramatzki ¶, Alan M. Krensky ||, and Irving L. Weissman * ${ddagger}$

*Departments of Pathology and Developmental Biology, Institute of Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 94305-5323; ${sect}$ Department of Functional Diagnostic Science, Osaka University School of Medicine, Osaka 565-0871, Japan; ¶Division of Stem Cell Transplantation and Immunotherapy, Second Department of Medicine, University of Kiel, Kiel 24105, Germany; and ||Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305

Contributed by Irving L. Weissman, May 10, 2007 (sent for review March 20, 2007)

Permanent cure of acute myeloid leukemia (AML) by chemotherapy alone remains elusive for most patients because of the inability to effectively eradicate leukemic stem cells (LSCs), the self-renewing component of the leukemia. To develop therapies that effectively target LSC, one potential strategy is to identify cell surface markers that can distinguish LSC from normal hematopoietic stem cells (HSCs). In this study, we employ a signal sequence trap strategy to isolate cell surface molecules expressed on human AML-LSC and find that CD96, which is a member of the Ig gene superfamily, is a promising candidate as an LSC-specific antigen. FACS analysis demonstrates that CD96 is expressed on the majority of CD34+CD38- AML cells in many cases (74.0 ± 25.3% in 19 of 29 cases), whereas only a few (4.9 ± 1.6%) cells in the normal HSC-enriched population (Lin-CD34+CD38-CD90+) expressed CD96 weakly. To examine whether CD96+ AML cells are enriched for LSC activity, we separated AML cells into CD96+ and CD96- fractions and transplanted them into irradiated newborn Rag2-/- ${gamma}$ c-/- mice. In four of five samples, only CD96+ cells showed significant levels of engraftment in bone marrow of the recipient mice. These results demonstrate that CD96 is a cell surface marker present on many AML-LSC and may serve as an LSC-specific therapeutic target.

Fig. 1. SST screening of CD34CD38 AML-LSCs. (A) The scheme of the SST
screening of CD34CD38 AML-LSCs. Full-length cDNA, either digested into
pieces (experiment 1, Left) or undigested (experiment 2, Right), was ligated
with a BstXI linker and subcloned into pMX-SST vector. TPOR, thrombopoietin
receptor (a constitutively active mutant); TM, transmembrane. (B) CD96mRNA
expression level in CD34CD38 cells from three different AML (M2) samples
and normal CD34CD38Lin cells. The expression levels are shown relative to
those in normal CD34CD38Lin BM cells.

英文全文链接：http://www.pnas.org/cgi/reprint/0704271104v1.pdf

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