生物谷报道:B细胞慢性淋巴细胞白血病(CLL)发病率相当高,但是在遗传学背景上一直没有找到与之对应的基因突变或变异。
由美国俄亥俄州立大学人类癌症遗传研究项目组Christoph Plass教授最近研究有明,这种白血病,可能与体一种死亡相关蛋白激酶1(DAPK1)活性下降有关。在发育过程中,如果DAPK1基因出现沉默或不表达时,将明显增加出生后的慢性淋巴细胞白血病。而且通过对DAPK1基因的深入研究,对CLL进行了基因分型的研究,为将来个性化治疗提供先期的探索。
如果在受精时,DAPK1基因的活率如果在精子细胞中下降了75%,将在生长发育过程中导致进一步表达降低,甚至失活,从而大大增加患CLL的可能性。当然,目前仍然不知道DAPK1下降是因还是果,需要更深和更广泛的研究问题。
原始出处:
The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 (DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAPK1 expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAPK1 expression. Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype.
原文链接:
Downregulation of Death-Associated Protein Kinase 1 (DAPK1) in Chronic Lymphocytic Leukemia.
Aparna Raval,1,10 Stephan M. Tanner,1 John C. Byrd,2 Elizabeth B. Angerman,1 James D. Perko,1 Shih-Shih Chen,1 Björn Hackanson,1,8 Michael R. Grever,2 David M. Lucas,2 Jennifer J. Matkovic,2 Thomas S. Lin,2 Thomas J. Kipps,6 Fiona Murray,7 Dennis Weisenburger,4 Warren Sanger,4 Jane Lynch,4 Patrice Watson,4 Mary Jansen,4 Yuko Yoshinaga,3 Richard Rosenquist,7 Pieter J. de Jong,3 Penny Coggill,5 Stephan Beck,5 Henry Lynch,4 Albert de la Chapelle,1,9, and Christoph Plass1
Cell, Vol 129, 879-890, 01 June 2007