Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia

Harry W. Findley, Lubing Gu, Andrew M Yeager, Muxiang Zhou

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

Bcl-2 and its homologue, Bcl-xl, encode membrane-associated proteins that protect neoplastic cells from DNA damage-induced apoptosis, whereas Bax is a Bcl-2 antagonist that promotes cell death. In the present study, we examined the expression and regulation of these genes at both the mRNA and protein level in 22 pediatric acute lymphoblastic leukemia (ALL) cell lines, as well as their sensitivity to apoptosis after exposure to ionizing radiation (IR). Eleven of 22 lines expressed wild-type (wt) p53, 4 expressed mutant p53, and 7 did not express p53 (p53-null). Nine of 22 (41%) lines expressed Bcl-2; of these, 8 were wt-p53+ and 1 expressed mutant p53. Bcl-2 was not expressed in any p53-null lines. In contrast, all 22 lines were positive for Bcl-xl and Bax, although expression level varied. Treatment with IR (10 Gy) induced both downregulation of Bcl-2 and upregulation of Bax at 2 to 5 hours post-IR in 5 of 8 (63%) wt-p53+ lines, leading to apoptosis. Conversely, lines that failed to both downregulate Bcl-2 and upregulate Bax after IR were resistant to apoptosis. Although levels of Bcl-xl expression varied among the 22 lines, high levels of Bcl-xl were observed in 5 of 7 (71%) p53- lines. There were no obvious changes in the expression of Bcl-xl in these lines after IR. However, among the p53-null lines, resistance to IR was observed only in those expressing high levels of Bcl-xl. These results suggest that expression of Bcl-2 but not Bcl-xl is p53-dependent and that IR- induced downregulation of Bcl-2 and upregulation of Bax occur in most wt- p53+ lines and are associated with radiosensitivity. Furthermore, high- level expression of Bcl-xl occurs predominantly in p53-null lines and is associated with resistance to IR-induced apoptosis in these lines, indicating differential expression and regulation of Bcl-2 and Bcl-xl in pediatric ALL.

Original languageEnglish (US)
Pages (from-to)2986-2993
Number of pages8
JournalBlood
Volume89
Issue number8
StatePublished - Apr 15 1997
Externally publishedYes

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Ionizing radiation
Ionizing Radiation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Apoptosis
Pediatrics
Up-Regulation
Down-Regulation
Radiation Tolerance
Gene Expression Regulation
Cell death
DNA Damage
Membrane Proteins
Cell Death
Genes
Cells
Cell Line
Messenger RNA
DNA

ASJC Scopus subject areas

  • Hematology

Cite this

Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia. / Findley, Harry W.; Gu, Lubing; Yeager, Andrew M; Zhou, Muxiang.

In: Blood, Vol. 89, No. 8, 15.04.1997, p. 2986-2993.

Research output: Contribution to journalArticle

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title = "Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia",
abstract = "Bcl-2 and its homologue, Bcl-xl, encode membrane-associated proteins that protect neoplastic cells from DNA damage-induced apoptosis, whereas Bax is a Bcl-2 antagonist that promotes cell death. In the present study, we examined the expression and regulation of these genes at both the mRNA and protein level in 22 pediatric acute lymphoblastic leukemia (ALL) cell lines, as well as their sensitivity to apoptosis after exposure to ionizing radiation (IR). Eleven of 22 lines expressed wild-type (wt) p53, 4 expressed mutant p53, and 7 did not express p53 (p53-null). Nine of 22 (41{\%}) lines expressed Bcl-2; of these, 8 were wt-p53+ and 1 expressed mutant p53. Bcl-2 was not expressed in any p53-null lines. In contrast, all 22 lines were positive for Bcl-xl and Bax, although expression level varied. Treatment with IR (10 Gy) induced both downregulation of Bcl-2 and upregulation of Bax at 2 to 5 hours post-IR in 5 of 8 (63{\%}) wt-p53+ lines, leading to apoptosis. Conversely, lines that failed to both downregulate Bcl-2 and upregulate Bax after IR were resistant to apoptosis. Although levels of Bcl-xl expression varied among the 22 lines, high levels of Bcl-xl were observed in 5 of 7 (71{\%}) p53- lines. There were no obvious changes in the expression of Bcl-xl in these lines after IR. However, among the p53-null lines, resistance to IR was observed only in those expressing high levels of Bcl-xl. These results suggest that expression of Bcl-2 but not Bcl-xl is p53-dependent and that IR- induced downregulation of Bcl-2 and upregulation of Bax occur in most wt- p53+ lines and are associated with radiosensitivity. Furthermore, high- level expression of Bcl-xl occurs predominantly in p53-null lines and is associated with resistance to IR-induced apoptosis in these lines, indicating differential expression and regulation of Bcl-2 and Bcl-xl in pediatric ALL.",
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AB - Bcl-2 and its homologue, Bcl-xl, encode membrane-associated proteins that protect neoplastic cells from DNA damage-induced apoptosis, whereas Bax is a Bcl-2 antagonist that promotes cell death. In the present study, we examined the expression and regulation of these genes at both the mRNA and protein level in 22 pediatric acute lymphoblastic leukemia (ALL) cell lines, as well as their sensitivity to apoptosis after exposure to ionizing radiation (IR). Eleven of 22 lines expressed wild-type (wt) p53, 4 expressed mutant p53, and 7 did not express p53 (p53-null). Nine of 22 (41%) lines expressed Bcl-2; of these, 8 were wt-p53+ and 1 expressed mutant p53. Bcl-2 was not expressed in any p53-null lines. In contrast, all 22 lines were positive for Bcl-xl and Bax, although expression level varied. Treatment with IR (10 Gy) induced both downregulation of Bcl-2 and upregulation of Bax at 2 to 5 hours post-IR in 5 of 8 (63%) wt-p53+ lines, leading to apoptosis. Conversely, lines that failed to both downregulate Bcl-2 and upregulate Bax after IR were resistant to apoptosis. Although levels of Bcl-xl expression varied among the 22 lines, high levels of Bcl-xl were observed in 5 of 7 (71%) p53- lines. There were no obvious changes in the expression of Bcl-xl in these lines after IR. However, among the p53-null lines, resistance to IR was observed only in those expressing high levels of Bcl-xl. These results suggest that expression of Bcl-2 but not Bcl-xl is p53-dependent and that IR- induced downregulation of Bcl-2 and upregulation of Bax occur in most wt- p53+ lines and are associated with radiosensitivity. Furthermore, high- level expression of Bcl-xl occurs predominantly in p53-null lines and is associated with resistance to IR-induced apoptosis in these lines, indicating differential expression and regulation of Bcl-2 and Bcl-xl in pediatric ALL.

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