生物谷报道：30年来，国内外科研人员在5号染色体一条“长臂”上，不断搜寻可能存在的白血病抑制基因而未能成功。如今，在中科院上海生命科学研究院、上海交大医学院共建的健康科学研究所，科学家经过三年努力，已经筛选并识别出-连结蛋白基因（alpha-catenin）可能就是那个血癌抑制基因。昨天记者从该所获悉，以其为第一单位的相关论文被新年首期国际权威学刊《自然·医学》（《Nature Medicine》）刊登。
人类染色体仿佛一枚枚不对称的“蝴蝶结”，拥有众多长臂和短臂。其中，5号染色体长臂（5q）会发生一种杂合性缺失，这是人类造血系统恶性疾病中最常见的染色体结构异常。尤其在恶性白血病患者中，其缺失率高达42％。因此，这一代号为“5q”的染色体长臂，便成为全球白血病研究人员的一个首选攻关目标。
健康科学所刘廷析研究员带领发育与疾病研究组，与哈佛大学医学院达纳法伯癌症研究所等多个实验室合作，针对5号染色体长臂的关键缺失区，反复研究其中的28个候选抑制基因，终于发现：人体造血干细胞中正常表达的-连结蛋白基因，在“5q”缺失的白血病肿瘤干细胞中表达显著下降，甚至丢失。从而证实，该基因与白血病关系密切。
这一研究阐明了关于白血病抑制基因失活的分子遗传学新机制。即一个-连结蛋白等位基因，会因基因组片段的缺失而失活，而另一个未缺失的-连结蛋白等位基因，也会因一种“表观遗传学机制”而被抑制。这种“双重打击”显示，人体正常造血干细胞的遗传学机制紊乱，可能在白血病肿瘤干细胞的恶性转化中起了重要作用。据悉，有关动物研究已在斑马鱼身上展开。
Figure 1. Purification and gene expression analysis of normal HSCs and L-ICs and dual-fluorescence in situ hybridization (D-FISH) analysis of HL-60 cells and purified L-ICs.
(a) Top, normal HSCs enriched for the CD34+CD38-CD90+Lin- fraction. Middle, L-ICs (CD34+CD38-CD123+Lin-) enriched from an individual with del(5q). Bottom, L-ICs (CD34+CD38-CD123+Lin-) from an individual lacking the del(5q). (b–d) D-FISH analysis of HL-60 cells and sorted del(5q) L-ICs from primary leukemia samples. Nuclei of the HL-60 cell line and del(5q) L-ICs from patients V, VII and VIII display two green dots (5p) and one red dot (5q), reflecting loss of one allele of the region of the probe within 164 kb of CTNNA1. (e–g) Non-del(5q) L-ICs from patients XIII and XXII show two green (5p15) and two red (5q31) dots, indicating intact chromosomes 5. (h) Expression profiles of 28 5q CDR genes in HSCs and del(5q)-derived L-ICs. The genes, as well as sequence tag site (STS) markers, are listed in the order of their physical positions (megabase, Mb) along chromosome 5q from centromere (upper) to telomere (bottom), according to the most recent human genome assembly at http://genome.ucsc.edu/. Previously defined 5q31 CDRs are shown schematically on the far left. GAPDH, which resides on chromosome 12, is included as a positive control. MT, verification that intron-spanning RT-PCR primers amplify each of the RNAs, by using a control cDNA prepared from a mixture of 22 human tissues. Single-step RT-PCR was performed with 10-cell aliquots (lanes 1 and 2) and without the RT step (lane –RT, negative control). Asterisks denote the genes expressed in normal HSCs and L-ICs, while the arrowhead indicates the CTNNA1 gene, which was expressed in HSCs, but not in the L-ICs of these three del(5q) individuals.
原文出处：
Nature Medcine January 2007, Volume 13 No 1
Chromosome 5q deletion and epigenetic suppression of the gene encoding -catenin (CTNNA1) in myeloid cell transformation pp78 - 83
Ting Xi Liu, Michael W Becker, Jaroslav Jelinek, Wen-Shu Wu, Min Deng, Natallia Mikhalkevich, Karl Hsu, Clara D Bloomfield, Richard M Stone, Daniel J DeAngelo, Ilene A Galinsky, Jean-Pierre Issa, Michael F Clarke & A Thomas Look
Published online: 10 December 2006 | doi:10.1038/nm1512
Abstract | Full text | PDF (491K) | Supplementary Information
