Acute myeloid leukemia (AML) is the most common (30-40%) of all leukemias and has the poorest survival (25%) of any leukemia. Mutations in the DNA methyltransferase DNMT3A and internal tandem duplications of the FLT3 receptor tyrosine kinase (FLT3-ITD) and are two of the most frequent events in over 50% of AML and commonly co-occur in patients conferring increased resistance to chemotherapy, the standard treatment for this subtype of AML. DNMT3A/FLT3-mutant AML have more adverse clinical outcome than AML with either mutation alone. Thus, there is a dire need for a better understanding of the biological mechanisms underlying this disease to address pressing therapeutic challenges. Our preliminary data suggest that DNMT3A/FLT3-ITD AML downregulate innate immune signaling through Toll-like receptors (TLRs) to maintain stemness and block differentiation. Our data also indicate that microRNA may play an important role in the dysregulation of TLR pathways in AML cells, suggesting a novel crosstalk between epigenetic/signaling mutations, microRNA, and innate immune signaling in AML. Despite evidence that suggests TLR signaling is an important contributor to the pathogenesis of myelodysplastic syndrome (MDS), very little is known about TLR signaling in AML. Thus, we are focusing on defining the mechanisms that deregulate TLR signaling in AML, understanding the consequences of suppressed TLR signaling in AML pathogenesis, and finally whether TLR signaling can be leveraged to treat AML.

Public Health Relevance

To address pressing prognostic and therapeutic needs in acute myeloid leukemia (AML), this project will elucidate the impact of non-coding RNA regulatory networks in the development and maintenance of high-risk AML. We have uncovered novel crosstalk between epigenetic/signaling mutations, non-coding RNA, and innate immune signaling. Specifically, the proposed work will test novel therapeutic combinations in a mouse model of a common, high-risk AML subtype to understand how innate immune signaling contributes to leukemia and treatment response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA226433-02
Application #
9728900
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Klauzinska, Malgorzata
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107