Acute Myeloid Leukemia Induces an Increased Senescent Phenotype in the Large Intestine Which Protects Barrier Function and Reduces Leakiness

The initiation and progression of multiple diseases and cancers has been associated with both intestinal dysfunction and microbiome changes, particularly those associated with aging, including acute myeloid leukemia (AML) (Wang et al., 2022). AML is a rapidly proliferating hematological malignancy, primarily affecting the elderly population, which interacts with and affects multiple organs in order to enhance its survival and ability to proliferate. One key hallmark of an aging phenotype is cellular senescence, defined as an irreversible state of cell cycle arrest in G1 phase, preventing cellular growth and division, as well as the secretion of a wide range of proinflammatory factors, creating a senescence-associated secretory phenotype (SASP). Our previous work has shown that AML can induce senescence in the bone marrow microenvironment, accelerating AML disease progression via the secretion of proinflammatory SASP-cytokines which support the survival and proliferation of AML blasts (Abdul-Aziz et al., 2019).

Multiple studies have linked AML to cellular and morphological alterations in the liver, spleen, central nervous system and kidneys. However, whether these changes are caused in the early stages of the disease to aid AML proliferation and survival or are just a consequence of late-stage AML and the associated multi-organ failure is hard to define. Very limited research has studied the impact of AML on the intestine and how these intestinal changes affect AML disease progression. Here, we investigate the role of AML on the intestine, and in particular the role of cellular senescence within the gut.

Intestines were harvested from two syngeneic mouse models of AML (MN1 and MEIS1/HOXA9), and intestinal epithelial cells were isolated from the colon. Analysis of the large intestine showed increased intestinal senescence, as evidenced by increased expression of p16 and p21 within intestinal epithelial cells, as well as positive Beta-galactosidase staining. This increase in senescence correlated with a significant decrease in proliferation by nearly 30% compared to control mice, evidenced by Ki67 immunohistochemistry. Increased senescence also correlated with increased tight junction RNA and protein expression. Immunofluorescent microscopy revealed there was a significant increase in zonula occludens-1 (ZO-1) and occludin expression in the intestinal epithelial cells at the tip of the colonic crypts, suggesting reduced overall gut leakiness within the colon of AML mice.

To investigate whether this increase of intestinal senescence was beneficial to or protective against the AML, mice engrafted with AML were orally treated with the senolytic, Navitoclax. Removal of senescent cells in large intestine, by Navitoclax, from tumor bearing mice was confirmed by decreased expression of p16 and p21, as well as negative Beta-galactosidase staining. Moreover, Navitoclax reduced expression of tight junction proteins occludin and ZO-1, suggesting an increased gut leakiness. This increased gut leakiness allowed the translocation of bacteria and their byproducts, evidenced by an increase of circulating LPS binding protein.

In conclusion, we have demonstrated that intestinal senescence occurs in the colon in response to AML, offering a protective effect by increasing tight junction protein expression and reducing gut leakiness. Pharmacological removal of these senescent cells damaged intestinal barrier function and resulted in increased gut leakiness. Further work needs to establish the impact of Navitoclax induced gut leakiness, via elimination of senescent intestine cells, on AML progression and tumor burden.

No relevant conflicts of interest to declare.