Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia

Xabier Agirre, José Román-Gómez, Iria Vázquez, Antonio Jiménez-Velasco, Leire Garate, Cristina Montiel-Duarte, Paula Artieda, Lucia Cordeu, Idoya Lahortiga, María José Calasanz, Anabel Heiniger, Antonio Torres, John D. Minna, Felipe Prósper

Research output: Contribution to journalArticle

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Abstract

The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in down-regulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm.

Original languageEnglish (US)
Pages (from-to)1945-1953
Number of pages9
JournalInternational Journal of Cancer
Volume118
Issue number8
DOIs
StatePublished - Apr 15 2006

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methylation
Down-Regulation
Gene Expression
Tumor Suppressor Genes
Blast Crisis
Lung
CpG Islands
Astrocytoma
Parkinsonian Disorders
Hematologic Neoplasms
Tumor Cell Line
Neuroblastoma
Genetic Promoter Regions
Colonic Neoplasms
Genes
Hepatocellular Carcinoma
Leukemia
Breast

Keywords

  • Common fragile site (CFS)
  • Fluorescence in situ hybridization (FISH)
  • Methylation
  • Methylation specific PCR (MSP)
  • Promoter

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia. / Agirre, Xabier; Román-Gómez, José; Vázquez, Iria; Jiménez-Velasco, Antonio; Garate, Leire; Montiel-Duarte, Cristina; Artieda, Paula; Cordeu, Lucia; Lahortiga, Idoya; Calasanz, María José; Heiniger, Anabel; Torres, Antonio; Minna, John D.; Prósper, Felipe.

In: International Journal of Cancer, Vol. 118, No. 8, 15.04.2006, p. 1945-1953.

Research output: Contribution to journalArticle

Agirre, X, Román-Gómez, J, Vázquez, I, Jiménez-Velasco, A, Garate, L, Montiel-Duarte, C, Artieda, P, Cordeu, L, Lahortiga, I, Calasanz, MJ, Heiniger, A, Torres, A, Minna, JD & Prósper, F 2006, 'Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia', International Journal of Cancer, vol. 118, no. 8, pp. 1945-1953. https://doi.org/10.1002/ijc.21584
Agirre, Xabier ; Román-Gómez, José ; Vázquez, Iria ; Jiménez-Velasco, Antonio ; Garate, Leire ; Montiel-Duarte, Cristina ; Artieda, Paula ; Cordeu, Lucia ; Lahortiga, Idoya ; Calasanz, María José ; Heiniger, Anabel ; Torres, Antonio ; Minna, John D. ; Prósper, Felipe. / Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia. In: International Journal of Cancer. 2006 ; Vol. 118, No. 8. pp. 1945-1953.
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abstract = "The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26{\%} of patients with acute lymphoblastic leukemia and 20{\%} of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in down-regulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm.",
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AU - Agirre, Xabier

AU - Román-Gómez, José

AU - Vázquez, Iria

AU - Jiménez-Velasco, Antonio

AU - Garate, Leire

AU - Montiel-Duarte, Cristina

AU - Artieda, Paula

AU - Cordeu, Lucia

AU - Lahortiga, Idoya

AU - Calasanz, María José

AU - Heiniger, Anabel

AU - Torres, Antonio

AU - Minna, John D.

AU - Prósper, Felipe

PY - 2006/4/15

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N2 - The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in down-regulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm.

AB - The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in down-regulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm.

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KW - Methylation

KW - Methylation specific PCR (MSP)

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