title: p15Ink4bLoss of Expression by Promoter Hypermethylation Adds to Leukemogenesis and Confers a Poor Prognosis in Acute Promyelocytic Leukemia Patients.
abstract: OBJECTIVE
  The p15Ink4bgene exerts its influence as an inhibitor of cyclin-dependent kinases and is frequently associated with hematological malignancies. Inactivation of this gene through DNA methylation has been found to be the most prevalent epigenetic alteration reported, with a high frequency in all French-American-British subtypes of acute myeloid leukemias, including acute promyelocytic leukemia (APL). In this study,we investigated the prognostic significance of p15 gene promoter hypermethylation and its expression in APL patients of Kashmir (North India).
  
  
  METHODS
  p15 gene promoter hypermethylation was conducted by methylation-specific polymerase chain reaction, while its subsequent expression analysiswas carried out by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  Of the 37 patients, 16 (43.2%) were found to have methylated p15 genes. Of these 16 cases, seven (43.8%) were methylated partially and nine (56.2%) were found to have complete methylation. Moreover, nine of the 37 patients (24.3%) who presented with leukocytosis at their baseline had complete p15 gene methylation as well (p < 0.05). Semiquantitative RT-PCR showed a complete loss of p15 expression in nine patients with complete methylation coupled with leukocytosis (p=0.031), while seven patients with partial methylation showed decreased p15 expression. Six patients relapsed during the maintenance phase of treatment and were found to have a completely methylated p15 gene and no p15 mRNA.
  
  
  CONCLUSIONS
  Complete methylation and loss of p15 gene expression causes susceptibility to relapse and decreased survival in APL patients. Thus, p15 promoter hypermethylation is a prospective prognostic indicator and a reliable clinical aid in assessment of patients with APL.
authors.affiliation: Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Baba
authors.affiliation: Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Niyaz A
authors.initials: NA
authors.lastname: Azad
authors.affiliation: Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Zafar A
authors.initials: ZA
authors.lastname: Shah
authors.affiliation: Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.lastname: Dil-Afroze
authors.affiliation: Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Arshad A
authors.initials: AA
authors.lastname: Pandith
authors.affiliation: Department of Clinical Hematology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Aleem
authors.initials: A
authors.lastname: Jan
authors.affiliation: Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Sheikh A
authors.initials: SA
authors.lastname: Aziz
mesh_terms: D000328:Adult; D015415:Biomarkers; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D055815:Young Adult
chemical_list: D015415:Biomarkers; D050762:Cyclin-Dependent Kinase Inhibitor p15
keywords: Acute promyelocytic leukemia; Arsenic tri-oxide; Kashmir; Leukocytosis; Promoter hypermethylation; p15Ink4b