Acute myeloid leukemia (AML) continues to have a dismal 5-years survival rate of <25% with chemotherapy. Those who survive suffer lifelong consequences, largely due to complications from chemotherapy, and disease relapse is inevitable. Thus, there is an urgent need for new, improved treatments to eliminate AML cells rapidly and completely. Since AML is a highly heterogeneous disease caused by multiple mutations, we propose that a common, targetable feature among AML cases is that they are directly and indirectly influenced by cytokines secreted in the bone marrow microenvironment. Our long-term goal is to identify novel drug targets to selectively eradicate malignant clones that may impact the response to AML therapies. Our immediate goals are to comprehensively determine the molecular mechanisms by which inflammatory pathways promote clonal evolution in AML. We found that the inflammatory cytokine interleukin-1? (IL-1?), which is elevated in a diverse set of AML patients, both encourages AML cells to multiply and simultaneously impedes normal cell growth. Blocking communication between AML cells and IL-1? inhibits these effects and reduces survival of AML cells while sparing healthy progenitors. Because cells from a majority of AML patients with different genetic subtypes are dependent on IL-1 signaling for their survival, we predict that a large percentage of AML patients might benefit from drugs targeting this pathway. However, direct targeting of IL-1 signaling may impact cellular functions in healthy cells. We therefore focused our study on defining the IL-1-mediated molecular differences between AML and healthy progenitors. Gene expression analysis identified that IL-1 upregulates ASF1B and MARCKS in AML compared to healthy progenitors. ASF1B and MARCKS regulate cell proliferation, DNA damage response, and inflammation in AML. Our data shows that genetic and pharmacological targeting of ASF1B and MARCKS pathways suppresses AML growth. These findings suggest a number of important new research directions. In the proposed project, we will test the hypothesis that differential activation of ASF1B and MARCKS by IL-1? in AML versus healthy progenitors provides a competitive advantage to leukemic cells, which ultimately leads to AML progression. Specifically, we will determine: (1) the in vitro mechanisms by which IL-1 activation of ASF1B and MARCKS promotes the growth of AML cells; (2) the roles of ASF1B and MARCKS in conferring IL-1-mediated growth advantage and driving AML progression in vivo; and (3) the validity of ASF1B and MARCKS as therapeutic targets in AML using available small-molecule inhibitors. To achieve our goals we established a variety of tools including 4 new transgenic mouse models and access to TLK and MARCKS inhibitor through collaborations with world-renowned leaders. Determining the underlying molecular mechanisms by which IL-1 supports AML development will pave the way to designing new treatment strategies.

Public Health Relevance

Successful treatment of acute myeloid leukemia (AML) using targeted agents has been impeded by both disease heterogeneity and drug resistance. To address this challenge, we will identify unique, targetable differences in pathways activated by inflammatory cytokines in AML cells but not in healthy cells, and we will identify the mechanisms by which these pathways selectively drive the course of disease in AML patients. This study will improve our understanding of AML biology and aid in the design of new treatment strategies that effectively target AML cells and suppress disease progression while minimizing side effects by sparing healthy cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA229875-01A1
Application #
9737704
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Klauzinska, Malgorzata
Project Start
2019-03-01
Project End
2024-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239