Acute myeloid leukemia induces pro-tumoral p16INK4a driven senescence in the bone marrow microenvironment

Abdul-Aziz, Amina M, Sun, Yu, Hellmich, Charlotte, Marlein, Christopher R, Mistry, Jayna, Forde, Eoghan, Piddock, Rachel E, Shafat, Manar S, Morfakis, Adam, Mehta, Tarang, Di Palma, Federica, Macaulay, Iain, Ingham, Christopher J, Haestier, Anna, Collins, Angela, Campisi, Judith, Bowles, Kristian M. and Rushworth, Stuart A (2019) Acute myeloid leukemia induces pro-tumoral p16INK4a driven senescence in the bone marrow microenvironment. Blood, 133 (5). pp. 446-456. ISSN 0006-4971

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Abstract

Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a 1 senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the “benign” senescent cells that surround and support AML.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 06 Dec 2018 17:30
Last Modified: 01 Jul 2020 23:52
URI: https://ueaeprints.uea.ac.uk/id/eprint/69189
DOI: 10.1182/blood-2018-04-845420

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