p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia

Alper Yetil, Benedict Anchang, Arvin M. Gouw, Stacey J. Adam, Tahera Zabuawala, Ramya Parameswaran, Jan van Riggelen, Sylvia Plevritis, Dean W. Felsher

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in siturecruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL.

Original languageEnglish (US)
Pages (from-to)3563-3577
Number of pages15
JournalOncotarget
Volume6
Issue number6
DOIs
StatePublished - Jan 1 2015

Keywords

  • ALL
  • MYC
  • Macrophage
  • P19ARF
  • P53
  • Senescence

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia'. Together they form a unique fingerprint.

  • Cite this

    Yetil, A., Anchang, B., Gouw, A. M., Adam, S. J., Zabuawala, T., Parameswaran, R., Riggelen, J. V., Plevritis, S., & Felsher, D. W. (2015). p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia. Oncotarget, 6(6), 3563-3577. https://doi.org/10.18632/oncotarget.2969