Methylation of the IL-12Rβ2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells

Irma Airoldi, Claudia Cocco, Emma Di Carlo, Silvia Disarò, Emanuela Ognio, Giuseppe Basso, Vito Pistoia

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Previous studies have shown that the interleukin-12 receptor β2 (IL-12Rβ2) gene is expressed in normal naive, germinal center and memory B cells but not in their malignant counterparts. The aim of this study was to investigate (i) whether the IL-12Rβ2 gene is silenced in B-cell acute lymphoblastic leukemia (B-ALL) cells, and (ii) what the functional implications of such silencing for tumor growth are. Here, we show that although mature B cells expressed both chains of the IL-12R, normal pro-B and pre-B cells failed to express the IL-12Rβ2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rβ2 chain. IL-12Rβ2 gene silencing in B-ALL was found to depend on methylation of a CpG island in exon 1. Such methylation was not detected in normal early B cells that when differentiated into mature B cells expressed the IL-12Rβ2 gene. Detection of IL-12Rβ2 mRNA and protein in the tumorigenic 697 pre-B-ALL cell line allowed to perform functional experiments in severe combined immunodeficient/ nonobese diabetic mice receiving 697 cells with or without human recombinant IL-12 (hrIL-12). hrIL-12 administration reduced tumor growth and metastasis through antiproliferative and proapoptotic rather than antiangiogenic, activities. In conclusion, epigenetic silencing of the IL-12Rβ2 gene represents a novel mechanism of tumor escape for B-ALL cells.

Original languageEnglish
Pages (from-to)3978-3980
Number of pages3
JournalCancer Research
Volume66
Issue number8
DOIs
Publication statusPublished - Apr 15 2006

Fingerprint

Interleukin-12 Receptors
Tumor Escape
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methylation
B-Lymphocytes
Pediatrics
Genes
B-Lymphoid Precursor Cells
Interleukin-12
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms
Inbred NOD Mouse
CpG Islands
Germinal Center
Gene Silencing
Growth
Epigenomics
Exons
Neoplasm Metastasis
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Methylation of the IL-12Rβ2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells. / Airoldi, Irma; Cocco, Claudia; Di Carlo, Emma; Disarò, Silvia; Ognio, Emanuela; Basso, Giuseppe; Pistoia, Vito.

In: Cancer Research, Vol. 66, No. 8, 15.04.2006, p. 3978-3980.

Research output: Contribution to journalArticle

Airoldi, Irma ; Cocco, Claudia ; Di Carlo, Emma ; Disarò, Silvia ; Ognio, Emanuela ; Basso, Giuseppe ; Pistoia, Vito. / Methylation of the IL-12Rβ2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells. In: Cancer Research. 2006 ; Vol. 66, No. 8. pp. 3978-3980.
@article{dff97674f6b14a48a3f2d4c40bc84ec2,
title = "Methylation of the IL-12Rβ2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells",
abstract = "Previous studies have shown that the interleukin-12 receptor β2 (IL-12Rβ2) gene is expressed in normal naive, germinal center and memory B cells but not in their malignant counterparts. The aim of this study was to investigate (i) whether the IL-12Rβ2 gene is silenced in B-cell acute lymphoblastic leukemia (B-ALL) cells, and (ii) what the functional implications of such silencing for tumor growth are. Here, we show that although mature B cells expressed both chains of the IL-12R, normal pro-B and pre-B cells failed to express the IL-12Rβ2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rβ2 chain. IL-12Rβ2 gene silencing in B-ALL was found to depend on methylation of a CpG island in exon 1. Such methylation was not detected in normal early B cells that when differentiated into mature B cells expressed the IL-12Rβ2 gene. Detection of IL-12Rβ2 mRNA and protein in the tumorigenic 697 pre-B-ALL cell line allowed to perform functional experiments in severe combined immunodeficient/ nonobese diabetic mice receiving 697 cells with or without human recombinant IL-12 (hrIL-12). hrIL-12 administration reduced tumor growth and metastasis through antiproliferative and proapoptotic rather than antiangiogenic, activities. In conclusion, epigenetic silencing of the IL-12Rβ2 gene represents a novel mechanism of tumor escape for B-ALL cells.",
author = "Irma Airoldi and Claudia Cocco and {Di Carlo}, Emma and Silvia Disar{\`o} and Emanuela Ognio and Giuseppe Basso and Vito Pistoia",
year = "2006",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-05-4418",
language = "English",
volume = "66",
pages = "3978--3980",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Methylation of the IL-12Rβ2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells

AU - Airoldi, Irma

AU - Cocco, Claudia

AU - Di Carlo, Emma

AU - Disarò, Silvia

AU - Ognio, Emanuela

AU - Basso, Giuseppe

AU - Pistoia, Vito

PY - 2006/4/15

Y1 - 2006/4/15

N2 - Previous studies have shown that the interleukin-12 receptor β2 (IL-12Rβ2) gene is expressed in normal naive, germinal center and memory B cells but not in their malignant counterparts. The aim of this study was to investigate (i) whether the IL-12Rβ2 gene is silenced in B-cell acute lymphoblastic leukemia (B-ALL) cells, and (ii) what the functional implications of such silencing for tumor growth are. Here, we show that although mature B cells expressed both chains of the IL-12R, normal pro-B and pre-B cells failed to express the IL-12Rβ2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rβ2 chain. IL-12Rβ2 gene silencing in B-ALL was found to depend on methylation of a CpG island in exon 1. Such methylation was not detected in normal early B cells that when differentiated into mature B cells expressed the IL-12Rβ2 gene. Detection of IL-12Rβ2 mRNA and protein in the tumorigenic 697 pre-B-ALL cell line allowed to perform functional experiments in severe combined immunodeficient/ nonobese diabetic mice receiving 697 cells with or without human recombinant IL-12 (hrIL-12). hrIL-12 administration reduced tumor growth and metastasis through antiproliferative and proapoptotic rather than antiangiogenic, activities. In conclusion, epigenetic silencing of the IL-12Rβ2 gene represents a novel mechanism of tumor escape for B-ALL cells.

AB - Previous studies have shown that the interleukin-12 receptor β2 (IL-12Rβ2) gene is expressed in normal naive, germinal center and memory B cells but not in their malignant counterparts. The aim of this study was to investigate (i) whether the IL-12Rβ2 gene is silenced in B-cell acute lymphoblastic leukemia (B-ALL) cells, and (ii) what the functional implications of such silencing for tumor growth are. Here, we show that although mature B cells expressed both chains of the IL-12R, normal pro-B and pre-B cells failed to express the IL-12Rβ2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rβ2 chain. IL-12Rβ2 gene silencing in B-ALL was found to depend on methylation of a CpG island in exon 1. Such methylation was not detected in normal early B cells that when differentiated into mature B cells expressed the IL-12Rβ2 gene. Detection of IL-12Rβ2 mRNA and protein in the tumorigenic 697 pre-B-ALL cell line allowed to perform functional experiments in severe combined immunodeficient/ nonobese diabetic mice receiving 697 cells with or without human recombinant IL-12 (hrIL-12). hrIL-12 administration reduced tumor growth and metastasis through antiproliferative and proapoptotic rather than antiangiogenic, activities. In conclusion, epigenetic silencing of the IL-12Rβ2 gene represents a novel mechanism of tumor escape for B-ALL cells.

UR - http://www.scopus.com/inward/record.url?scp=33646247193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646247193&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-4418

DO - 10.1158/0008-5472.CAN-05-4418

M3 - Article

VL - 66

SP - 3978

EP - 3980

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 8

ER -