Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies

Zijun Y. Xu-Monette, L. Jeffrey Medeiros, Yong Li, Robert Z. Orlowski, Michael Andreeff, Carlos E. Bueso-Ramos, Timothy Charles Greiner, Timothy J. McDonnell, Ken H. Young

Research output: Contribution to journalReview article

89 Citations (Scopus)

Abstract

Mutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability, and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.

Original languageEnglish (US)
Pages (from-to)3668-3683
Number of pages16
JournalBlood
Volume119
Issue number16
DOIs
StatePublished - Apr 19 2012

Fingerprint

Transcription
Tumor Suppressor Genes
Tumors
Genes
Lymphoma
Neoplasms
Chemical activation
Apoptosis
Sequence Deletion
p53 Genes
Autophagy
Metabolism
Gene expression
DNA Repair
Cell Cycle
Cytoplasm
Repair
Cells
Clinical Trials
Gene Expression

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Xu-Monette, Z. Y., Jeffrey Medeiros, L., Li, Y., Orlowski, R. Z., Andreeff, M., Bueso-Ramos, C. E., ... Young, K. H. (2012). Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood, 119(16), 3668-3683. https://doi.org/10.1182/blood-2011-11-366062

Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. / Xu-Monette, Zijun Y.; Jeffrey Medeiros, L.; Li, Yong; Orlowski, Robert Z.; Andreeff, Michael; Bueso-Ramos, Carlos E.; Greiner, Timothy Charles; McDonnell, Timothy J.; Young, Ken H.

In: Blood, Vol. 119, No. 16, 19.04.2012, p. 3668-3683.

Research output: Contribution to journalReview article

Xu-Monette, ZY, Jeffrey Medeiros, L, Li, Y, Orlowski, RZ, Andreeff, M, Bueso-Ramos, CE, Greiner, TC, McDonnell, TJ & Young, KH 2012, 'Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies', Blood, vol. 119, no. 16, pp. 3668-3683. https://doi.org/10.1182/blood-2011-11-366062
Xu-Monette ZY, Jeffrey Medeiros L, Li Y, Orlowski RZ, Andreeff M, Bueso-Ramos CE et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood. 2012 Apr 19;119(16):3668-3683. https://doi.org/10.1182/blood-2011-11-366062
Xu-Monette, Zijun Y. ; Jeffrey Medeiros, L. ; Li, Yong ; Orlowski, Robert Z. ; Andreeff, Michael ; Bueso-Ramos, Carlos E. ; Greiner, Timothy Charles ; McDonnell, Timothy J. ; Young, Ken H. / Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. In: Blood. 2012 ; Vol. 119, No. 16. pp. 3668-3683.
@article{155b4ea0135f4240a3ed9e4c9c133e92,
title = "Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies",
abstract = "Mutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability, and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.",
author = "Xu-Monette, {Zijun Y.} and {Jeffrey Medeiros}, L. and Yong Li and Orlowski, {Robert Z.} and Michael Andreeff and Bueso-Ramos, {Carlos E.} and Greiner, {Timothy Charles} and McDonnell, {Timothy J.} and Young, {Ken H.}",
year = "2012",
month = "4",
day = "19",
doi = "10.1182/blood-2011-11-366062",
language = "English (US)",
volume = "119",
pages = "3668--3683",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "16",

}

TY - JOUR

T1 - Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies

AU - Xu-Monette, Zijun Y.

AU - Jeffrey Medeiros, L.

AU - Li, Yong

AU - Orlowski, Robert Z.

AU - Andreeff, Michael

AU - Bueso-Ramos, Carlos E.

AU - Greiner, Timothy Charles

AU - McDonnell, Timothy J.

AU - Young, Ken H.

PY - 2012/4/19

Y1 - 2012/4/19

N2 - Mutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability, and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.

AB - Mutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability, and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.

UR - http://www.scopus.com/inward/record.url?scp=84860329005&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860329005&partnerID=8YFLogxK

U2 - 10.1182/blood-2011-11-366062

DO - 10.1182/blood-2011-11-366062

M3 - Review article

VL - 119

SP - 3668

EP - 3683

JO - Blood

JF - Blood

SN - 0006-4971

IS - 16

ER -