Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy and the most common adult acute leukemia. While therapeutic benefits are seen initially, clinical outcomes are unacceptable. Thus, cancer prevention could be an alternative approach to benefit AML patients. However, the unavailability of risk factors and early symptoms in AML patients hampers the design of cancer prevention strategies. Mounting evidence indicates that aberrant DNA methylation appears in early-stage AML and represents plausible mechanisms underlying initiation of carcinogenesis and cancerous lesions. DNA methylation is susceptible to change by environmental factors, but which and how environmental factors regulate DNA methylation patterning in AML cells are unclear. Our preliminary studies show that DNMT1 is upregulated and the levels of DNA methylation are increased in high-fat diet-induced obese mice compared to lean mice, supporting that lipid abnormality could play in the regulation of DNA methylation. Our data also show that obese AML patients and mice develop worse leukemic disease with a shorter survival time than lean subjects. Although many factors in obesity are altered, IL-6, a key pro-inflammatory cytokine, could be the primary molecule linking obesity to AML cell onset and disease progression. In line with this, obese mice and patients are frequently associated with elevated serum concentration of saturated fatty acids (SFA), which stimulate the secretion of cytokines (e.g., IL-6), when compared to lean counterparts. IL-6 is also abundantly expressed in AML cells, and importantly, IL- 6 overexpression predicts worse outcomes in AML patients. Treatment with obesity-relevant IL-6 protein is sufficient to increase AML cell multiplication, but IL-6 knockdown in AML cells significantly inhibits AML cell growth. Mechanistic investigation shows that IL-6 protein promotes DNMT1 expression coupled by an increase of DNA methylation. Given the important role of a pro-inflammatory cytokines and the aberrant DNA methylation in carcinogenesis and tumorigenesis, we hypothesize that IL-6-DNA methylation axis links SFA aberrations in obesity to aggressive AML pathogenesis. Pharmacological inhibition of IL-6 induces DNA hypomethylation and blocks AML progression. To test this hypothesis, we are proposing two aims: 1) To determine whether and how SFA abnormality augments AML leukemia; 2) To perform preclinical in vivo evaluation of IL-6 inhibitor in AML mice. We anticipate that IL-6-DNA methylation axis represents a novel mechanism underlying obesity-cancer association and a unique risk factor for AML prevention. We also anticipate that IL-6 inhibitor restrains the proliferation of AML cells through its DNA hypomethylating activity, and thereby, serving as a practical leukemia treatment regimen.

Public Health Relevance

Due to the lack of primary risk factors and disease symptoms, preventing leukemia is a difficult battle. This project investigates the molecular mechanisms underlying obesity-associated AML leukemia progression and establishes the clinical feasibility of targeting cytokine/DNA methylation axis for leukemia prevention. Our findings will identify risk factors, targets and medicinal agents to efficiently treat leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA186176-01A1
Application #
9172103
Study Section
Special Emphasis Panel (ZCA1-SRB-L (M1))
Program Officer
Ross, Sharon A
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$77,500
Indirect Cost
$27,500
Name
University of Minnesota Twin Cities
Department
Type
Organized Research Units
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455