Zhang (Chengcheng "Alec") Lab

Meet the Principal Investigator

Dr. Alec Zhang

Dr. Alec Zhang

Dr. Zhang is the Hortense L. and Morton H. Sanger Professorship in Oncology and the Michael L. Rosenberg Scholar in Medical Research. His research interest is focused on ITIM-receptors and ligands in cancer and immunity.

Phone: 214-645-6320
Fax: 214-648-1960
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Lab Members

Samuel John, M.D.

Assistant Professor
2015-present
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Samuel John, M.D.

Jingjing Xie, Ph.D.,

Assistant Instructor
2014-present
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Jingjing Xie, Ph.D.

Xiaoye Liu, Ph.D.

Postdoc Fellow
2016-present
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Xiaoye Liu, Ph.D.

Ryan Huang, B.S.

Graduate Student
2019-present
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Ryan Huang, B.S.

Yubo "David" He, B.S.

Student
2019-present
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Yubo "David" He, B.S.

Caroline Smith, M.D.

Pediatric Fellow
2021-present
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Caroline Smith, M.D.

Chengcheng Zhang, Ph.D.

Postdoc Associate
2022-present
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Chengcheng Zhang, Ph.D.

Bruce Zhang, B.S.

Technical Assistant
2022-present
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Bruce Zhang, B.S.

Zade Sadek

Medical student intern
2022
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Zade Sadek

Research Interest

The long-term goal of our laboratory is to illuminate the function of immune surface molecules and to open up a new research field at the interface of cancer, immunology, and stem cell research. We are also actively developing novel therapies for cancer treatment.

    The leukocyte Ig-like receptor subfamily B (LILRB) proteins are primate-specific, type I transmembrane glycoproteins. The extracellular Ig-like domains of these proteins bind ligands, and their intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) can recruit phosphatases SHP-1, SHP-2, or SHIP. We have been studying the roles of this family of immune checkpoint receptors in leukemia development and in tumor microenvironment of solid cancers. We demonstrated that several receptors in this family, including LILRB1, LILRB2, LILRB4, and LAIR1, inhibit immune responses and support tumor development. LILRBs thus have dual concordant roles in tumor biology – as immune checkpoint molecules and as tumor-sustaining factors. LILRBs may represent ideal targets for tumor treatment. Targeting LILRBs may perfectly combine immunotherapy and targeted therapy, and lead to the development of novel therapies for cancer treatment.

    In addition to LILRB2, we are identifying additional receptors for various angiopoietin-like proteins. We are studying the function of these ligands and receptors in cancer, stem cells, and immunity.

    We demonstrated that the immune privilege of HSCs can be regulated by controlling surface expression of the immune inhibitor PD-L1, and ex vivo expanded HSCs efficiently overcome MHC barrier and engraft allogeneic recipient mice.

    How dietary restrictions affect hematopoietic malignancies are unknown. We showed that fasting alone robustly inhibits initiation and reverses later development of acute lymphoblastic leukemia (both B-ALL and T-ALL) but not acute myeloid leukemia (AML). Fasting blocks ALL development by upregulation of leptin receptor (LepR) and its downstream signaling through Prdm1. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and suggest new avenues for development of novel strategies for leukemia treatment.

    Awards and honors

    • Basil O'Connor Scholar
    • American Society of Hematology Junior Faculty Scholar
    • New Investigator Award
      American Cancer Society/ UT Southwestern
    • Michael L. Rosenberg Scholar in Biomedical Research
      UT Southwestern
    • Howard Temin KO1 award
      National Cancer Institute
    • Gabrielle’s Angel Foundation for Cancer Research Fellow
    • Royan International Research Award
    • Leukemia & Lymphoma Society Scholar Award
    • Hortense L. and Morton H. Sanger Professorship in Oncology

    News

    Researchers find potential new way to target lethal form of leukemia

    UT Southwestern scientists, working with colleagues at a sister institution in Houston, have identified a new target for battling a deadly form of leukemia.

    The findings raise the possibility of a novel treatment for this subtype of blood and bone marrow cancer – known as acute myeloid leukemia or AML – by attacking a harmful molecule found on the cancerous cells and also reactivating the body’s white blood cells to fight them.

    Immune-Onc Therapeutics and University of Texas Report a Novel Target for Acute Myeloid Leukemia in Nature

    The study, led by The University of Texas Southwestern Medical Center (“UT Southwestern”) and The University of Texas Health Science Center at Houston (“UTHealth”), demonstrated that leukocyte immunoglobulin-like receptor B4 (LILRB4), an immune inhibitory receptor, orchestrates leukemia invasion pathways by creating an immune suppressive microenvironment. Researchers discovered that blocking LILRB4 signaling with antagonistic antibodies can impede AML development in preclinical models, making it a compelling therapeutic target.

    Scientists identify key receptors behind development of acute myeloid leukemia

    UT Southwestern Medical Center scientists have discovered that a certain class of receptors that inhibit immune response are crucial for the development of acute myeloid leukemia (AML), the most common acute leukemia affecting adults.

    Researchers found that some receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are important to the development of AML, providing a target for potential therapies.

    Fasting kills cancer cells of most common type of childhood leukemia

    UT Southwestern Medical Center researchers have found that intermittent fasting inhibits the development and progression of the most common type of childhood leukemia.

    This strategy was not effective, however, in another type of blood cancer that commonly strikes adults.

    Researchers identify immune inhibitory receptors that bind to ANGPTLS and support leukemia development

    An immune-system receptor plays an unexpected but crucially important role in keeping stem cells from differentiating and in helping blood cancer cells grow, researchers at UT Southwestern Medical Center report today in the journal Nature.

    Researchers find way to help donor adult blood stem cells overcome transplant rejection

    Findings by UT Southwestern Medical Center researchers may suggest new strategies for successful donor adult stem cell transplants in patients with blood cancers such as leukemia, lymphoma and myeloma.

    The study, published Aug. 5 in Cell Stem Cell, showed for the first time that adult blood stem cells can be regulated to overcome an immune response that leads to transplant rejection. It also opens up further studies in stem cell immunology, said Dr. Chengcheng "Alec" Zhang, assistant professor of physiology and developmental biology at UT Southwestern and senior author of the study.

    Selected Publications (of a total of 109)

    1. Zhang CC, Krieg S, and Shapiro DJ. 1999. HMG-1 Stimulates Estrogen Response Element Binding by Estrogen Receptor from Stably Expressed HeLa Cells. Molecular Endocrinology 13: 632-643.
    2. Zhang CC and Shapiro DJ. 2000. Activation of the p38 Mitogen-activated Protein Kinase Pathway by Estrogen or by 4-Hydroxy Tamoxifen is Coupled to Estrogen Receptor-induced Apoptosis. Journal of Biological Chemistry 275: 479-486.
    3. Zhang CC, Glenn K, Kuntz M, and Shapiro DJ. 2000. High Level Expression of Full-length Estrogen Receptor in E. coli is Facilitated by the Uncoupler of Oxidative Phosphorylation, CCCP. Journal of Steroid Biochemistry and Molecular Biology 74: 169-178.
    4. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB. 2002. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A  99: 16309-16313.
    5. Zhang CC and Lodish HF. 2004. Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 103: 2513-2521.
    6. Zhang CC and Lodish HF. 2005. Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion. Blood 105: 4314-4320.
    7. Thomas M, Lu JJ, Ge Q, Zhang CC, Chen J, Klibanov AM. 2005. Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung. Proc Natl Acad Sci U S A  102: 5679-5684.
    8. Zhang CC, Kaba M, Ge G, Xie K, Tong W, Hug C, Lodish HF. 2006. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nature Medicine 12: 240-245.
    9. Zhang CC, Steele AD, Lindquist S, Lodish HF. 2006. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc Natl Acad Sci U S A 103: 2184-2189.
    10. Liao MJ*, Zhang CC*, Zhou B*, Zimonjic DB, Mani SA, Kaba M, Gifford A, Reinhardt F, Popescu NC, Guo W, Eaton EG, Lodish HF, Weinberg RA. 2007. Enrichment of a population of mammary gland cells that forms mammospheres and has in vivo repopulating activity. Cancer Res. 67: 8131-8138 (* first authors).
    11. Zhang CC*, Kaba M, Iizuks S, Huynh H, Lodish HF*. 2008. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells.  Blood 111: 3415-3423 (* corresponding authors)
    12. Zhang CC and Lodish HF. 2008. Cytokines regulation of hematopoietic stem cell functions. Current Opinion in Hematology 15: 307-311.
    13. Huynh H, Iizuka S, Kaba M, Kirak O, Zheng J, Lodish HF, Zhang CC. 2008. IGFBP2 secreted by a tumorigenic cell line supports ex vivo expansion of mouse hematopoietic stem cells. Stem Cells 26: 1628-1635.
    14. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. 2008. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704-715.
    15. Patrick DM, Zhang CC, Tao Y, Yao H, Qi X, Schwarz RJ, Huang LJ, Olson EN. 2010. Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3z. Genes and Development 24:1614-1619.
    16. Simsek T, Kocabas F, Zheng J, DeBerardinis RJ, Olson EN, Schneider JW, Zhang CC*, Sadek HA*. 2010. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7:380-390. (* corresponding authors)
    17. Zheng J, Huynh H, Umikawa M, Silvany R, Zhang CC. 2011. Angiopoietin-like protein 3 supports the activity of mouse hematopoietic stem cells in the bone marrow niche. Blood 117:470-479
    18. Zheng J, Umikawa M, Zhang S, Huynh H, Silvany R, Chen BPC, Chen L, Zhang CC. 2011. Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell 9:119-130 
    19. Huynh H, Zheng J, Umikawa M, Zhang C, Silvany R, Iizuka S, Holzenberger M, Zhang W, Zhang CC. 2011. IGF Binding Protein 2 Supports the Survival and Cycling of Hematopoietic Stem Cells. Blood 118:3236-3243 
    20. Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, Huynh H, Kang X, Silvany R, Wan X, Ye J, Canto AP, Chen SH, Wang HY, Ward ES, Zhang CC. 2012. Inhibitory receptors bind Angptls and support blood stem cells and leukemia development. Nature 485:656-660 
    21. Kocabas F, Zheng J, Thet S, Copeland NG, Jenkins NA, DeBerardinis RJ, Zhang CC*, Sadek HA*. 2012. Meis1 regulates the metabolic phenotype and oxidative defense of hematopoietic stem cells. Blood. 120(25):4963-72 (*corresponding authors)
    22. Zhang CC, Sadek H. 2014. Hypoxia and Metabolic Properties of Hematopoietic Stem Cells. Antioxidants & Redox Signaling.  20(12):1891-1901
    23. Zheng J, Lu Z, Kocabas F, Bottcher RT, Costell M, Kang X, Liu X, DeBerardinis RJ, Wang Q, Chen G, Sadek H, Zhang CC. 2014. Profilin-1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow. Blood. 123: 992-1001
    24. Zhang CC. 2014. Novel signaling axis in CML-initiating cells. Blood. 123: 2443-2445
    25. Deng M*, Lu Z*, Zheng J, Wan X, Chen X, Hirayasu K, Sun H, Lam Y, Chen L, Wang Q, Song C, Huang N, Gao GF, Jiang Y, Arase H, Zhang CC. 2014. A motif in LILRB2 critical for Angptl2 binding and activation. Blood. 124(6):924-35
    26. Yu X, Wang Y, Deng M, Li Y, Ruhn KA, Zhang CC, Hooper LV. 2014. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. eLife. 10.7554/eLife.04406
    27. Kocabas F, Zheng J, Zhang CC, Sadek HA. 2014. Metabolic characterization of hematopoietic stem cells. Methods in Molecular Biology. 1185:155-164.
    28. Kang X, Cui C, Lu Z, Dong B, Han X, Tyner JW, Coligan JE, Collins R, You JM, Zhang CC. 2015. The ITIM-containing receptor LAIR1 is essential for acute myeloid leukemia development. Nature Cell Biology. 17(5):665-677
    29. Lin MI, Price EN, Boatman S, Hagedorn EJ, Trompouki E, Satishchandran S, Carspecken CW, Uong A, DiBiase A, Yang S, Canver MC, Dahlberg A, Lu Z, Zhang CC, Orkin SH, Bernstein ID, Aster JC, White RM, Zon LI. 2015 Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling. eLife. 10.7554/eLife.05544
    30. Kimura W, Xiao F, Canseco DC, Muralidhar S, Thet S, Zhang HM, Abderrahman Y, Chen R, Garcia JA, Shelton JM, Richardson JA, Ashour AM, Asaithamby A, Liang H, Xing C, Lu Z, Zhang CC, Sadek HA. 2015. Hypoxia fate-mapping identifies cycling cardiomyocytes in the adult heart. Nature. 523(7559):226-23
    31. Kang X, Kim J, Deng M, John S, Chen H, Wu G, Phan H, Zhang CC. 2016. Inhibitory leukocyte immunoglobulin-like receptors: immune checkpoint proteins and tumor sustaining factors. Cell Cycle. 15(1):25-40 
    32. Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, Shah A, Zhang H, Faber JE, Kinter MT, Szweda LI, Xing C, Deberardinis R, Oz O, Lu Z, Zhang CC, Kimura W, Sadek HA. 2017. Hypoxia induces heart regeneration in adult mice. Nature. 541(7636):222-227
    33. Lu Z, Xie J, Wu G, Shen J, Collins R, Chen W, Kang X, Luo M, Zou Y, Huang LJ, Amatruda JF, Slone T, Winick N, Scherer PE, Zhang CC. 2017. Fasting selectively blocks acute lymphoblastic leukemia development via leptin receptor upregulation. Nature Medicine. 23(1):79-90
    34. John S, Chen H, Deng M, Gui X, Wu G, Chen W, Li Z, Zhang N, An Z, Zhang CC. 2018. A novel anti-LILRB4 CAR-T cell for the treatment of monocytic AML. Molecular Therapy. 26(10):2487-2495

    35. Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, He L, Chen Y, Chen H, Luo W, Lu Z, Xie J, Churchill H, Xu Y, Zhou Z, Wu G, Yu C, John S, Hirayasu K, Nguyen N, Liu X, Huang F, Li L, Deng H, Tang H, Sadek AH, Zhang L, Huang T, Zou Y, Chen B, Zhu H, Arase H, Xia N, Jiang Y, Collins R, You MJ, Homsi J, Unni N, Lewis C, Chen GQ, Fu YX, Liao XC, An Z, Zheng J, Zhang N, Zhang CC.2018. LILRB4 signaling in leukemia cells mediatesT cell suppression and tumor infiltration. Nature. 562(7728):605-609
    36. Gui X, Deng M, Song H, Chen Y, Xie J, Li Z, He L, Huang E, Xu Y, Anami Y, Yu H, Yu C, Li L, Yuan Z, Xu X, Wang Q, Chai Y, Huang T, Shi Y, Tsuchikama K, Liao XC, Xia N, Gao GF, Zhang N, Zhang CC, An Z. 2019. Disrupting LILRB4/APOE interaction by an efficacious humanized antibody reverses T cell suppression and blocks AML development. Cancer Immunology Research. 7(8):1244-1257
    37. Jiang W, Feng M, Kim B, Zhang CC, Fu YX, Weissman I. 2019. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nature Reviews Cancer.

      19 (10), 568-586

    38. Wu G, Zhang CC. 2020. Membrane protein CAR promotes hematopoietic regeneration upon stress. Hematologica. 2019.243998
    39. Chen H, Chen Y, Deng M, John S, Gui X, Kansagra A, Chen W, Kim J, Lewis C, Wu G, Xie J, Zhang L, Huang R, Liu X, Arase H, Huang Y, Yu H, Luo W, Xia N, Zhang N, An Z, Zhang CC. 2020. An antagonistic anti-LILRB1 monoclonal antibody regulates anti-tumor functions of natural killer cells. Journal for ImmunoTherapy of Cancer. 8(2):e000515
    40. Anami Y, Deng M, Gui X, Yamaguchi A, Yamazaki CM, Zhang N, Zhang CC*, An Z*, Tsuchikama K*. 2020. LILRB4-targeting Antibody–Drug Conjugates for the Treatment of Acute Myeloid Leukemia. Molecular Cancer Therapeutics. 19(11):2330-2339
    41. Deng M, Chen H, Liu X, Huang R, He Y, Yoo B, Xie J, John S, Zhang N, An Z, Zhang CC. 2021. Leukocyte immunoglobulin-like receptor subfamily B (LILRB): therapeutic targets in cancer. Antibody Therapeutics. 4(1):16-33
    42. Wu G, Xu Y, Schultz RD, Chen H, Xie J, Deng M, Liu X, Gui X, Jogn S, Lu Z, Arase H, Zhang N, An Z, Zhang CC. 2021. LILRB3 supports acute myeloid leukemia development and regulates T cell anti-tumor immune responses through the TRAF2-cFLIP-NFkB signaling axis. Nature Cancer. https://doi.org/10.1038/s43018-021-00262-0.