Ji Zhang, PhD

Bio

Dr. Zhang's laboratory uses biochemical, cellular and molecular biology and mouse genetic approaches to understand the fundamental mechanisms that underlie tumor cells' response to various metabolic stresses.

Dr. Zhang received his Ph.D. from the University of Tennessee Health Science Center, where he conducted his graduate thesis on the role of mitochondrial quality control machinery during red blood cell maturation. Dr. Zhang pursued his post-doctoral training with Dr. Craig Thompson, a world-renowned investigator in the field of cancer metabolism, at Memorial Sloan Kettering Cancer Center, New York, NY, to expand his research repertoire on nonessential amino acid metabolism in cancer. Dr. Zhang became an Assistant Professor of Pediatrics at Indiana University School of Medicine in 2017. Recently, the Zhang lab discovered that DNA hypomethylation in the promoter region of the asparagine synthetase (ASNS) gene plays a critical role in driving chemo-resistance in leukemia patients (Jiang et.al, 2019). In addition, the Zhang lab found that asparagine restriction effectively perturbs oncogenic MYC function in lymphoma/leukemia cells and has a therapeutic implication (Srivastava et.al, 2022). Furthermore, the Zhang lab has extensively collaborated with other labs on amino acid metabolism and adaptive stress responses in solid tumors, immune cells and stem cells.

Dr. Zhang has received several nationwide career development awards, including the Emerging Scientist Award from Children's Cancer Research Fund, Scholar Award from St. Baldrick’s Foundation and Scholar Award for Junior Faculty from American Society of Hematology.

Key Publications

Jiang J, Srivastava S, Liu S, Seim G, Claude G, Zhong M, Cao S, Davé U, Kapur R, Mosley AL, Zhang C, Wan J, Fan J, Zhang J. Asparagine starvation suppresses histone demethylation through iron. iScience. 2023; 26(4): 106425

Halbrook CJ, Thurston G, McCarthy A, Nelson BS, Sajjakulnukit P, Krall AS, Mullen PJ, Zhang L, Batra S, Viale A, Stanger BZ, Christofk HR, Zhang J, di Magliano MP, Jorgensen C, Lyssiotis CA. Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer. Nature Cancer. 2022; 3(11): 1386-1403

Ramdas B, Palam L, Singh-Mali R, Pasupuleti SK, Zhang J, Kelley M, Paczesny S, Zhang C, Kapur R. Combined heterozygosity of FLT3ITD TET2 and DNMT3A results in aggressive leukemia in mice and humans utilizing similar genetic programs. Journal of Clinical Investigation Insight. 2022; 7(18): e162016. doi: 10.1172/jci.insight.162016.

Srivastava S, Jiang J, Misra J, Seim G, Staschke KA, Zhong M, Zhou L, Liu Y, Chen C, Davé U, Kapur R, Batra S, Zhang C, Zhou J, Fan J, Wek RC, Zhang J. Asparagine bioavailability regulates the translation of MYC oncogene. Oncogene. 2022; 41(44): 4855-4865

Ramdas B, Yuen LD, Palam L, Patel R, Pasupuleti SK, Jideonwo V, Zhang J, Maguire C, Wong E, Zhang C, Sandusky G, Chan Rebecca, Zhang C, Stieglitz E, Haneline L, Kapur R. Inhibition of BTK and PI3Kδ impairs the development of Human JMML Stem and Progenitor cells. Molecular Therapy. 2022; 30(7): 2505-2521

Jiang J, Srivastava S, Seim G, Pavlova NN, King B, Zou L, Zhang C, Zhong M, Feng H, Kapur R, Wek RC, Fan J, Zhang J. Promoter demethylation of the asparagine synthetase gene is required for an ATF4-dependent adaptation to asparagine depletion. Journal of Biological Chemistry. 2019; 294(49):18674-18684

Jiang J, Srivastava S, Zhang J. (Review) Starve Cancer Cells of Glutamine: Break the Spell or Make a Hungry Monster? Cancers. 2019 Jun 11;11(6). pii: E804. doi: 10.3390/cancers11060804

As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Hui S, Ghergurovich JM, Fan J, Intlekofer AI, White RM, Rabinowitz JD, Thompson CB^§ , Zhang J^§ (§ co-corresponding author). Cell Metabolism. 2018; 27 (2): 428-438. PMCID: PMC5803449

Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. Zhang J, Pavlova NN, Thompson CB. The EMBO journal. 2017; 36(10):1302-1315. PMID: 28420743

Repression by RB1 characterizes genes involved in the penultimate stage of erythroid development. Zhang J, Loyd MR, Randall MS, Morris JJ, Shah JG, Ney PA. Cell Cycle. 2015;14(21):3441-53.

Serine catabolism regulates mitochondrial redox control during hypoxia. Ye J, Fan J, Venneti S, Wan YW, Pawel B, Zhang J, Finley LWS, Lu C, Lindsten T, Cross JR, Qing G, Liu Z, Simon MC, Rabinowitz JD, Thompson CB. Cancer Discovery. 2014; 4(12):1406-1417.

Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B, Djaballah H, Kanai M, Cheng EH, Judkins AR, Pawel B, Baggs J, Cherry S, Rabinowitz JD, Thompson CB. Molecular cell. 2014; 56(2):205-18. PMID: 25242145

Titles & Appointments

Assistant Professor of Pediatrics

Education

2017 FEL Cancer Biology and Genetics Research Fellowship, Memorial Sloan Kettering Cancer Center

2011 FEL Postdoctoral Fellowship, University of Pennsylvania

2010 FEL Biochemistry Postdoctoral Fellowship, St. Jude Children's Research Hospital

2008 PhD University of Tennessee

2002 BS Nanjing University
Research

Three major research projects in Dr. Zhang's lab are:

(1). Understand the mechanism of resistance to L-asparaginase treatment in pediatric acute lymphoblastic leukemia (ALL). L-asparaginase is used to treat pediatric ALL patients. However, resistance can occur to compromise the therapeutic efficacy. We are using cell culture, mouse ALL models and patient samples to understand the molecular mechanism that drives resistance to L-asparaginase treatment with the goal of identifying new therapeutic targets to enhance the efficacy of L-asparaginase.

(2). Elucidate the interplay between oncogenic signaling and nutrient acquisition/utilization in lymphoid malignacies. It is well-accepted that oncogenic signaling reprograms tumor cell metabolism to support growth and survival under nutrient limiting environment. However, whether nutrient availability can modulate oncogenic signaling as a means of metabolic adaptation has not been extensively explored. Using B cell lymphoma as a model, we will explore the molecular connections as well as potential therapeutic implication.

(3). Explore the role of nonessential amino acid metabolism in normal hematopoiesis. Hematopoiesis in adult originates from bone marrow where nutrient and oxygen are thought to be limited. As a result, understanding the metabolic regulation of normal hematopoiesis has become an emerging topic recently. Using mouse genetic models with deficiency on specific metabolic pathways we will investigate the role of nonessential amino acid metabolism in hematopoietic stem cell maintenance and differentiation.
Clinical Interests

In collaboration with Dr. Sandeep Batra at Riley Children's Hospital, and Dr. Utpal Davé at IU Simon Cancer Center, we are interested in understanding the genetic and epigenetic components that contribute to L-asparaginase sensitivity in pediatric and adult patient with lymphoblastic leukemia/lymphoma.
Awards

Org: NIH/NCI
Desc: 1R01 CA244625
Scope: National
Date: 2019-12-01

Org: American Society of Hematology
Desc: Junior Faculty Scholar Award
Scope: National
Date: 2019-07-01

Org: St. Baldrick’s Foundation
Desc: St. Baldrick’s Scholar Award
Scope: National
Date: 2018-07-01

Org: Children's Cancer Research Fund
Desc: Emerging Scientist Award
Scope: National
Date: 2018-03-01

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