Acute myeloid leukemia (AML) accounts for more than 40% of leukemia mortality in the United States. Each year around ten thousand people die from the disease, most within a few years of diagnosis. Despite advances in our understanding of the disease, few improvements in the therapy of AML have been made. Specific targets and novel strategies to eliminate AML stem cells are required for AML treatment. In preliminary studies, the PI?s lab has observed the following: 1) The expression of DPP4 negatively correlates with AML patient overall survival in 3 different databases. 2) DPP4 inhibitors can prevent AML development in vivo. 3) DPP4 inhibitors can prevent both human and mouse AML cells growth in vitro. 4) DPP4 knock out (KO) AML cells transplanted mice exhibit delay and reversal of AML development in two retroviral-induced AML mouse models. 5) DPP4 KO AML stem cells and progenitors (AML-SCP) are restrained in the bone marrow, with increased apoptosis, and reduced self-renewal ability. 6) DPP4 knockdown prevents the growth of human AML cells. 7) The activation of Src, IkB, and p65 is reduced in DPP4 KO AML cells. Based on these preliminary data, the central hypothesis is: DPP4 regulated trafficking, activation and apoptosis of AML-SCPs are critical for human AML development, which will be addressed in three specific aims.
Aim 1 : Determine the role of DPP4 in human AML development. The localization, apoptosis, and self-renewal of DPP4 deficient human AML-SCP will be investigated by colony forming unit assay and human AML cells xenografted mouse model. Using the xenograft model, the effect of DPP4 inhibitors treatment alone or in combination with standard chemotherapy to prevent AML development will be evaluated.
Aim 2 : Examine regulation of AML- SCP engraftment to the BM by DPP4. This will include identification of the critical cytokines regulated by DPP4 for AML-SCP trafficking. To test this, the PI will use migration and engraftment assays. In addition, the PI will investigate localization and niche cells interaction of DPP4 KO AML-SCPs in the BM microenvironment by imaging studies.
Aim3 : Investigate the role of DPP4 in AML-SCP survival. We will explore the critical domain of DPP4, if DPP4-Src interaction is essential for AML-SCP survival, how DPP4 regulates the activity and protein level of Src in AML-SCP and determine if dual therapy with DPP4 and Src inhibitors has greater benefits against human AML-SCP survival. Collectively, the proposed research will broadly impact the field by identification of a novel treatment for AML, via the strategy of confinement of AML-SCP to bone marrow, and improving the understanding of the role of microenvironment in the development of AML-SCPs.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with no major progress in therapy in the past 20 years. The lack of specific targets, and an understanding of the molecular and cellular mechanisms of AML stem cells (AML-SC) restrict the development of treatments to improve the outcome. The proposed studies aim to identify the utility of DPP4 inhibitors (a useful type two diabetes medicine) in human AML treatment and to understand the role of DPP4 in the regulation of AML development.
