title: Aberrant DNA methylation and epigenetic inactivation of hMSH2 decrease overall survival of acute lymphoblastic leukemia patients via modulating cell cycle and apoptosis.
abstract: OBJECTIVE
  Altered regulation of many transcription factors has been shown to play important roles in the development of leukemia. hMSH2 can modulate the activity of some important transcription factors and is known to be a regulator of hematopoietic differentiation. Herein, we investigated epigenetic regulation of hMSH2 and its influence on cell growth and overall survival of acute lymphoblastic leukemia (ALL) patients.
  
  
  METHODS
  hMSH2 promoter methylation status was assessed by COBRA and pyrosequencing in 60 ALL patients and 30 healthy volunteers. mRNA and protein expression levels of hMSH2, PCNA, CyclinD1, Bcl-2 and Bax were determined by real time PCR and Western blotting, respectively. The influence of hMSH2 on cell proliferation and survival was assessed in transient and stable expression systems.
  
  
  RESULTS
  mRNA and protein expression of hMSH2 and Bcl-2 was decreased, and that of PCNA, CyclinD1 and Bax was increased in ALL patients as compared to healthy volunteers (P<0.05). hMSH2 was inactivated in ALL patients through promoter hypermethylation. Furthermore, hMSH2 hypermethylation was found in relapsed ALL patients (85.7% of all cases). The median survival of patients with hMSH2 methylation was shorter than that of patients without hMSH2 methylation (log-rank test, P=0.0035). Over-expression of hMSH2 in cell lines resulted in a significant reduction in growth and induction of apoptosis.
  
  
  CONCLUSIONS
  This study suggests that aberrant DNA methylation and epigenetic inactivation of hMSH2 play an important role in the development of ALL through altering cell growth and survival.
authors: Department of Internal Medicine, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China E-mail : zhouzhiheng_00@163.com.
authors: Cai-Xia
authors: CX
authors: Wang
authors: Xiang
authors: X
authors: Wang
authors: Hai-Bai
authors: HB
authors: Liu
authors: Zhi-Heng
authors: ZH
authors: Zhou
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012008:Recurrence; D015996:Survival Rate; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein