Scientists from the University of East Anglia (UEA) say that leukemia promotes premature aging in healthy bone marrow cells. Their study (“Acute myeloid leukemia induces pro-tumoral p16INK4a driven senescence in the bone marrow microenvironment”), published in Blood, shows that healthy bone marrow cells were prematurely aged by cancer cells around them.
It is well known that aging promotes cancer development. But this is the first time that the reverse has been shown to be true. The aged bone marrow cells accelerated the growth and development of the leukemia, creating a vicious cycle that fuels the disease.
The study identified the mechanism by which this process of premature aging occurs in the bone marrow of leukemia patients and highlights the potential impact this could have on future treatments.
“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,” wrote the investigators.
“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.”
The research was led by Stuart Rushworth, PhD, from UEA’s Norwich Medical School, in collaboration with the Earlham Institute and the Norfolk and Norwich University Hospital and the Buck Institute for Research on Aging in California.
“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,” said Rushworth. “Our research reveals that leukemia uses this biological phenomenon to its advantage to accelerate the disease.”
NOX2, 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 research team established that the NOX2 enzyme generates superoxide which drives the aging process.
By inhibiting NOX2, researchers showed the reduction in aged neighboring non-malignant cells resulted in slower cancer growth.
According to Rushworth, “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.”
