Priority Research Papers:
p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia
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Alper Yetil1, Benedict Anchang2, Arvin M. Gouw1, Stacey J. Adam1, Tahera Zabuawala1, Ramya Parameswaran1, Jan van Riggelen1, Sylvia Plevritis2, Dean W. Felsher1
1Division of Oncology, Departments of Medicine and Pathology, Molecular Imaging Program, Stanford University, Stanford, California, United States of America
2Department of Radiology, Stanford University, Stanford, California, United States of America
Dean W. Felsher, e-mail: firstname.lastname@example.org
Keywords: MYC, p19ARF, ALL, senescence, macrophage
Received: November 04, 2014 Accepted: December 17, 2014 Published: January 13, 2015
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 important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL.
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