Every year, approximately 200,000 children and adults around the world die from leukemia. The most common leukemia -acute myeloid leukemia (AML) is propagated by small population of leukemia stem cells (LSC). The FMS-like tyrosine kinase-3 (FLT3) Internal tandem duplication (ITD) represents the most frequent mutation seen in AML patients with high risk of relapse. The FLT3-ITD mutation results in constitutive FLT3 tyrosine kinase (TK) activation. Persistent FLT3-ITD+ AML LSCs represent a reservoir of disease and source of relapse after treatment. However, FLT3 TK inhibitors (TKI) only modestly inhibit primary AML FLT3-ITD+ LSC growth and fail to demonstrate effective, long-term clinical activity. Therefore, additional therapeutic strategies are required to improve outcomes for FLT3-ITD+ AML patients. In preliminary studies I have found that the SIRT1 deacetylase is overexpressed in FLT3-ITD+ AML LSC, and SIRT1 inhibition significantly reduces growth and survival of AML LSC compared to normal stem cells. The studies also suggest that p53 acetylation and activation may play an important role in mediating the effects of SIRT1 inhibition on AML progenitors. In addition, the studies suggest that SIRT1 inhibition significantly further enhances inhibition of AML LSC growth by FLT3 TKI. Therefore, I hypothesize that SIRT1 activation with suppression of p53 activity is required for FLT3-ITD+ LSC maintenance; and that SIRT1 inhibition in combination with TKI could lead to elimination of FLT3-ITD+ AML LSC. Here I propose to determine the role of SIRT1 and p53 in regulating growth of FLT3/ITD+ AML LSCs in vivo (Aim1) in the mentored phase, and with this information in hand, I will then investigate mechanisms underlying SIRT1 upregulation in FLT3-ITD+ AML cells and evaluate whether SIRT1 inhibition can enhance elimination of AML LSCs in combination with TKI (Aim2) in the independent phase.
In Aim1, I will use a well-characterized FLT3-ITD+ murine transduction and transplantation AML model to test the effect of genetic deletion of SIRT1 on FLT3/ITD+ AML LSC. I will use a conditional p53 expression mouse model to determine the role of p53 activation, as opposed to other SIRT1 targets, in mediating pro-survival effects of SIRT1.
In Aim2, I will investigate SIRT1 regulatory pathway especially FLT3 kinase independent factors which would provide molecular rationale to combine SIRT1 and FLT3 inhibitors together to target FLT3- ITD AML LSC. Then I will directly test whether the combination of SIRT1 inhibition with FLT3 TKI can effectively target AML LSC in murine AML model as well as primary human AML xenograft model. The proposed studies will determine whether SIRT1 is a valid therapeutic target in AML LSC, and evaluate whether the combination of TKI and SIRT1 inhibitors represents an innovative and safe approach to effectively target FLT3-ITD+ AML LSC. I am motivated by a lifelong goal to create novel targeted therapeutics for leukemia. The short-term career goal is to establish a translational laboratory that provides an interface between basic biology and drug discovery. Both scientific and career developments are essential components to achieve this aim. Dr. Bhatia's lab at City of Hope (COH) provides such an environment to support the candidate's objectives of understanding the disease mechanisms and developing clinical relevant models to identify possible treatments. Also important elements such as mentorship from an established committee, advanced training in translational research, and incurring relevant scientific management skills would be utilized for the overall career development. All those components will ultimately help me to procure a faculty position in an environment supportive of translational research. COH, a NCI-designated Cancer Center is well known for its success in performing innovative investigator-initiated clinical trials for hematological malignancy that translate findings from laboratory into the clini. Working in this environment I have already made the important findings in chronic myeloid leukemia (CML) stem cells. Recently I turned my focus to AML, because in contrast to CML, the outcomes for AML treatment still remain very poor. Without understanding of mechanisms of maintenance and drug resistance of AML LSC, scientists can't develop any effective approaches to achieve potential cure of AML. Hence, it is evident that working on AML LSC biology would be an excellent focus for my future career development. Therefore, the present project will allow me to establish my independent expertise separate from my mentor's expertise in CML.
The presence of a FLT3 Internal tandem duplication (ITD) which is the most frequent mutation in (acute myeloid leukemia) AML patients, is a poor prognostic feature in AML, predicting increased relapse rates and reduced overall survival. Several potent FLT3 inhibitors in clinical trials demonstrate only limited clinical activity, suggesting additional novel therapeutic strategies are required to improve outcomes for FLT3-ITD+ AML patients. The proposed studies will provide preclinical proof-of-concept that combination of a novel targeted strategy-SIRT1 inhibition with FLT3 inhibitors represents an innovative approach to effectively treat FLT3-ITD+ AML patients.
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|Li, Ling; Osdal, Tereza; Ho, Yinwei et al. (2014) SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell Stem Cell 15:431-446|