Background: Acute myeloid leukemia (AML) is a common disease with over 70% of patients cannot be cured. Thus, it is urgent to develop effective new therapies. The TET (TET1/2/3) proteins are a family of methylcytosine dioxygenases involving DNA demethylation. In contrast to the tumor-suppressor roles of TET genes reported previously, we found that TET1 is significantly up-regulated and functions as a critical oncogene in MLL-rearranged AMLs (Huang et al. PNAS, 2013). We have recently found that TET1 is also up- regulated in AMLs carrying t(8;21), in which TET1 likely also plays an essential oncogenic role. Moreover, we have identified NSC-370284 as a lead small-molecule compound that selectively represses TET1 signaling and effectively inhibits growth of AML cells with a high level of endogenous TET1 expression. Hypothesis: TET1 plays a critical oncogenic role in the pathogenesis of not only MLL-rearranged AMLs but also t(8;21) AMLs, and targeting TET1 signaling by selective small-molecule compound(s) represents an effective novel therapeutic strategy to treat these AMLs.
Specific Aims : 1) To determine the definitive role of TET1 in both development and maintenance of t(8;21) AMLs, and identify critical target genes of TET1 in t(8;21) AMLs; 2) To decipher the molecular mechanism by which the lead compound (NSC-370284) inhibits TET1 signaling and exhibits an anti-leukemia activity; and 3) To develop novel therapies targeting TET1 signaling to treat MLL-rearranged AMLs and t(8;21) AMLs. Study Design: 1) First, to determine the role of TET1 in both development and maintenance of the major subtypes of t(8;21) AMLs, we will conduct both primary and secondary mouse bone marrow transplantation (BMT) assays using wild-type and Tet1 knockout mouse models together with retrovirally induced major subtypes of t(8;21) AML models. Second, to identify critical target genes of TET1 in t(8;21) AML, ChIP-Seq, 5hmC-Seq and RNA-Seq will be conducted. 2) Our preliminary data suggests that NSC-370284 likely targets SATA5 directly and thereby inhibits TET1 transcription. Here we will conduct a series of structural-functional studies, biochemical and pharmaceutical assays, and gene transcriptional regulation assays to determine whether STAT5 is a critical direct target of NSC-370284 and also a direct upstream regulator of TET1. Meanwhile, we will also conduct a series of assays to identify other potential direct targets of NSC-370284. 3) We will first assess pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and toxicity profile of NSC-370284 in vivo. We will then employ a series of preclinical animal models to evaluate the therapeutic efficacy and potential of NSC-370284, alone and especially together with other therapeutic agent(s), in treating both MLL-rearranged AMLs and t(8;21) AMLs in vivo. Thereafter, we will further optimize 370284 by chemical modifications to improve the potency, selectivity, and/or pharmacokinetic parameters. The anti-leukemia effects of a set of top derivatives will be evaluated in vivo.

Public Health Relevance

Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancies with the majority (>70%) of patients cannot be cured with contemporary therapies, and thus effective novel targeted therapies are urgently needed. The major goals of this proposal are to investigate the role and underlying mechanism of TET1 in AMLs with TET1 overexpression, and to test therapeutic potential of targeting TET1 signaling with small-molecule inhibitors. Thus, the success of this project will not only provide profound novel insights into the molecular mechanisms underlying leukemogenesis, but may also lead to the development of effective novel therapeutic strategies to treat AMLs, and therefore it is of great significance in both basic research and clinical/translational research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA211614-05
Application #
10067522
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Chen, Weiwei
Project Start
2017-01-01
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Deng, Xiaolan; Su, Rui; Weng, Hengyou et al. (2018) RNA N6-methyladenosine modification in cancers: current status and perspectives. Cell Res 28:507-517
Deng, Xiaolan; Su, Rui; Stanford, Savanna et al. (2018) Critical Enzymatic Functions of FTO in Obesity and Cancer. Front Endocrinol (Lausanne) 9:396
Su, Rui; Dong, Lei; Li, Chenying et al. (2018) R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling. Cell 172:90-105.e23
Deng, Xiaolan; Su, Rui; Feng, Xuesong et al. (2018) Role of N6-methyladenosine modification in cancer. Curr Opin Genet Dev 48:1-7
Jiang, Xi; Hu, Chao; Ferchen, Kyle et al. (2018) Author Correction: Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun 9:670
Huang, Huilin; Weng, Hengyou; Sun, Wenju et al. (2018) Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 20:285-295
Weng, Hengyou; Huang, Huilin; Wu, Huizhe et al. (2018) METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification. Cell Stem Cell 22:191-205.e9
Jiang, Xi; Hu, Chao; Ferchen, Kyle et al. (2017) Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun 8:2099
Li, Zejuan; Weng, Hengyou; Su, Rui et al. (2017) FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase. Cancer Cell 31:127-141
Li, Jing; Volk, Andrew; Zhang, Jun et al. (2017) Sensitizing leukemia stem cells to NF-?B inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling. Oncotarget 8:8420-8435

Showing the most recent 10 out of 11 publications