Leukemia Prematurely Ages Bone Marrow Cells

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells.

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).

A large team of scientists led by those at the University of East Anglia (Norwich, UK) identified the mechanism by which the process of premature aging occurs in the bone marrow of leukemia patients and highlights the potential impact this could have on future treatments. They reported 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.

The team next found that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. NADPH oxidase (NOX2) is an enzyme usually involved in the body’s response to infection, was shown to be present in AML cells, and this was found to be responsible for creating the aging conditions. The team established that the NOX2 enzyme generates superoxide, which drives the aging process. Finally, using the p16-3MR mouse model, they showed that by targeting NOX2, they reduced BM stromal cell senescence and consequently reduced AML proliferation. The data identifies leukemia generated NOX2 derived superoxide as a driver of pro-tumoral p16INK4a-dependent senescence in bone marrow stromal cells.

Stuart A. Rushworth, PhD, the lead author of the study, said, “Our results provide evidence that cancer causes aging. We have clearly shown that the cancer cell itself drives the aging process in the neighboring noncancer cells. Our study reveals that leukemia uses this biological phenomenon to its advantage to accelerate the disease. It was not previously known that leukemia induces aging of the local noncancer environment. We hope that this biological function can be exploited in the future, paving the way for new drugs.” The study was published on January 31, 2019, in the journal Blood.

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University of East Anglia