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

Amina M Abdul-Aziz, Yu Sun, Charlotte Hellmich, Christopher R Marlein, Jayna Mistry, Eoghan Forde, Rachel E Piddock, Manar S Shafat, Adam Morfakis, Tarang Mehta, Federica Di Palma, Iain Macaulay, Christopher J Ingham, Anna Haestier, Angela Collins, Judith Campisi, Kristian M. Bowles and Stuart A Rushworth

Key points

  • Leukemia blasts derived superoxide induces a senescent phenotype in cells within the bone marrow microenvironment

  • Targeting the senescent bone marrow cells improves the survival of mice with leukemia.

Abstract

Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of pro-inflammatory 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 bone marrow microenvironment. We report that the bone marrow stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feedback to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a-positive senescent bone marrow 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 bone marrow stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia generated NOX2 derived superoxide as a driver of pro-tumoral p16INK4a-dependent senescence in bone marrow 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 which specifically target the 'benign' senescent cells that surround and support AML.

  • Submitted April 16, 2018.
  • Accepted October 31, 2018.