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
Alper YetilDean W Felsher

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 situ recruitment 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 importan...Continue Reading

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Citations

Nov 1, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Takeshi YamadaMasakatsu Yamashita
Mar 9, 2018·Blood·Stephanie C CaseyDean W Felsher
Sep 29, 2015·Aging·Alper Y KearneyDean W Felsher
May 13, 2017·Veterinary Pathology·Peter VogelJerold E Rehg
Jan 17, 2019·Physiological Reviews·Arianna CalcinottoAndrea Alimonti
Dec 22, 2020·Journal of the Formosan Medical Association = Taiwan Yi Zhi·Tong-Hong WangChi-Yuan Chen

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Datasets Mentioned

BETA
GSE11877

Methods Mentioned

BETA
transgenic
Flow cytometry
FACS
PCR

Software Mentioned

Genespring
MetaMorph
Graph Pad Prism
CellQuest
Spot Advanced
FlowJo
Illumina Bead Studio

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