Previous studies by our laboratory and others have showed that chronic lymphocytic leukemia (CLL) cells exhibit elevated ROS generation, and that this oxidative stress renders the leukemia cell highly dependent on cellular antioxidant systems such as glutathione (GSH) to maintain redox balance and cell viability. Our recent study further showed that CLL cells were highly dependent on the bone marrow stromal cells to alleviate oxidative stress and promote their survival and drug resistance through enhancing GSH synthesis mediated by an intercellular metabolic communication involving cystine cysteine conversion and shuttling between the two cell compartments. These research findings provide new mechanistic insights into the biochemical interaction between leukemia and stromal cells. Importantly, the dependency of CLL cells on stromal cells for redox balance and cell survival has revealed an Achilles heel of CLL cells that can be targeted for therapeutic purpose. The main goal of this research project is to test the hypothesis that the metabolic communication between bone marrow stromal cells and CLL cells in cystine/cysteine/GSH metabolism can be used as a novel mechanism to selectively kill the leukemia cells using agents that preferentially impact the leukemia cells in the stromal environment. We propose to investigate the three Specific Aims: (1) Develop a novel mechanism- based therapeutic strategy to utilize the stromal-CLL intercellular interaction in cystine cysteine GSH metabolism as a unique pathway to convert the cystine analogs to toxic metabolites capable of selectively killing leukemia cells in the stromal microenvironment. (2) Investigate the high therapeutic selectivity of the cystine analogs that preferentially targets CLL cells in the presence of stromal cells, and exam the underlying mechanisms. (3) Use several CLL mouse models to test the in vivo therapeutic activity of the novel agents that by hijacking the stromal-CLL intercellular metabolic pathway to effectively kill CLL cells in the stromal microenvironment in vivo. Significance: This study will significantly advance our understating of leukemia-stromal interaction at biochemical levels and the role of such intercellular metabolic communication in leukemia cell survival and drug resistance. This study will also lead to the development of novel therapeutic strategies to effectively kill CLL in stromal microenvironment in vivo. Currently there is no effective therapy to overcome CLL drug resistance caused by the protective stromal microenvironment. The propose study will fill this significant gap by developing a novel strategy to turns the protective stromal cells into a metabolic machinery that produces active metabolite to selectively kill leukemia cells in tissue microenvironment, and thus will have important therapeutic implications in clinical treatment of CLL patients.

Public Health Relevance

Chronic lymphocytic leukemia (CLL) cells are under intrinsic oxidative stress and highly depend on cellular glutathione to maintain redox balance. Based on our recent discovery of a novel stromal- leukemia interaction mechanism in which the bone marrow stromal cells provide cysteine for CLL cells to synthesize glutathione to maintain redox balance and promotes cell survival and drug resistance, we now propose to take advantage of this stromal-CLL metabolic interaction and design a new mechanism-based therapeutic strategy using a novel agent to effectively target CLL cells in the stromal microenvironment without significant toxicity to normal cells. This new approach will significantly improve the in vivo therapeutic activity and selectivity, and thus have important therapeutic implications in clinical treatment of this most common adult leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA172724-05
Application #
9612522
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Alley, Michael C
Project Start
2015-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Yilei; Shi, Jiejun; Liu, Xiaoguang et al. (2018) BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol 20:1181-1192
Liao, Jianwei; Liu, Pan-Pan; Hou, Guoxin et al. (2017) Regulation of stem-like cancer cells by glutamine through ?-catenin pathway mediated by redox signaling. Mol Cancer 16:51
Cramer, Shira L; Saha, Achinto; Liu, Jinyun et al. (2017) Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat Med 23:120-127
Yang, Mengqi; Liu, Panpan; Wang, Kefeng et al. (2017) Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 expression in bone marrow stromal cells. Mol Oncol 11:358-372
Ju, Huai-Qiang; Ying, Haoqiang; Tian, Tian et al. (2017) Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma. Nat Commun 8:14437
Liu, P-P; Liu, J; Jiang, W-Q et al. (2016) Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene 35:5663-5673
Ogasawara, Marcia A; Liu, Jinyun; Pelicano, Helene et al. (2016) Alterations of mitochondrial biogenesis in chronic lymphocytic leukemia cells with loss of p53. Mitochondrion 31:33-39
Liu, Jinyun; Chen, Gang; Pelicano, Helene et al. (2016) Targeting p53-deficient chronic lymphocytic leukemia cells in vitro and in vivo by ROS-mediated mechanism. Oncotarget 7:71378-71389
Wang, Peng; Song, Ming; Zeng, Zhao-lei et al. (2015) Identification of NDUFAF1 in mediating K-Ras induced mitochondrial dysfunction by a proteomic screening approach. Oncotarget 6:3947-62
Yuan, Shuqiang; Lu, Yunxin; Yang, Jing et al. (2015) Metabolic activation of mitochondria in glioma stem cells promotes cancer development through a reactive oxygen species-mediated mechanism. Stem Cell Res Ther 6:198