UW madison
UW School of Medicine and Public Health
Carbone Cancer Center

Jing Zhang, Ph.D.

Jing Zhang
Centennial Professor of Oncology
Developmental Therapeutics Program Leader - UW Carbone Cancer Center

B.S., 1995, Biochemistry and Molecular Biology, Beijing University, China
Ph.D., 2001, Pharmacology, University of Pennsylvania School of Medicine
Postdoctoral research: Whitehead Institute for Biomedical Research, Boston, MA

7453 Wisconsin Institutes for Medical Research
Office - (608) 263-1147; Lab - (608) 263-1150
Research Description: 

The most fascinating feature of adult stem cells is their ability to replace themselves through many, but limited, rounds of self-renewal while also generating more differentiated progenies to constitute part of or entire tissues. When oncogenic mutations accumulate in normal stem cells, limited self-renewal evolves into “indefinite” self-renewal in prospective cancer stem cells. This leads to tumorigenesis in several organs.

My laboratory focuses on studying the mechanisms underlying the normal as well as oncogenic self-renewal of stem cells using the hematopoietic compartment as a model system. The hematopoietic system is one of the best tissues to study normal stem cells and prospective cancer stem cells; the developmental hierarchy of normal blood formation is well defined, hematopoietic stem cells (HSCs) can be highly purified based on their characteristic immunophenotypes, HSCs can be cultured in vitro, exogenous genes and shRNAs can be readily introduced into HSCs, and stem cell activities can be assayed by in vivo repopulation experiments in mouse. HSCs constantly make a choice between self-renewal and lineage differentiation, and the lineage-committed progenitors make a decision to proliferate, differentiate, or undergo apoptosis. This balance is critical because, once the balance is tilted towards “indefinite” self-renewal at the expense of normal terminal lineage differentiation, normal hematopoiesis evolves into hematopoietic malignancies.

HSCs are regulated by cell-cell and cell-extracellular matrix interactions as well as by cytokines acting through their receptors. One of the molecules we have been studying is K-ras. K-ras is one of the most frequently mutated genes identified in human patients with various hematopoietic malignancies. The oncogenic mutations in the K-ras gene are acquired either as the first genetic change (1st hit) during leukemogenesis or one of the later genetic changes during leukemia progression. However, its precise roles in leukemogenesis and leukemia progression remain elusive. Using recipient mice transplanted with bone marrow cells expressing oncogenic K-ras from its endogenous promoter, we found that oncogenic K-ras mutations induce hematopoietic malignancies in multiple lineages. Based on our preliminary results, we hypothesize that when oncogenic K-ras mutations act as the 1st hit in leukemogenesis, its primary target is HSCs. Oncogenic K-ras mutations further co-operate with additional genetic change(s) occurring in lineage-committed progenitors to initiate and maintain hematopoietic malignant phenotypes. Current projects include:

  1. Establish a model of oncogenic K-ras-induced hematopoietic malignancies
  2. Study the role of cytokine signaling in oncogenic K-ras-induced hematopoietic malignancies
  3. Establish a mouse model of acute myeloid leukemia by combining oncogenic N-ras mutation with Evi-1 overexpression
  4. Determine the roles of key signaling proteins and transcription factors in normal hematopoiesis and hematopoietic malignancies by creating and analyzing conditional knockout, oncogenic, or overexpression alleles
  5. Preclinical/translational studies using genetically modified mouse models of hematopoietic malignancies
Selected Recent Publications: 


Kong G, You X, Wen Z, Chang YI, Qian S, Ranheim EA, Letson C, Zhang X, Zhou Y, Liu Y, Rajagopalan A, Zhang J, Stieglitz E, Loh M, Hofmann I, Yang D, Zhong X, Padron E, Zhou L, Pear WS, Zhang J. Downregulating Notch counteracts Kras(G12D)-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm. Leukemia. 2019 Mar;33(3):671-685. doi: 10.1038/s41375-018-0248-0. Epub 2018 Sep 11. PubMed PMID: 30206308; PubMed Central PMCID: PMC6405304.

Soukup AA, Zheng Y, Mehta C, Wu J, Liu P, Cao M, Hofmann I, Zhou Y, Zhang J, Johnson KD, Choi K, Keles S, Bresnick EH. Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer. J Clin Invest. 2019 Mar 1;129(3):1180-1192. doi: 10.1172/JCI122694. Epub 2019 Feb 11. PubMed PMID: 30620726; PubMed Central PMCID: PMC6391105.

You X, Wen Z, Chang YI, Ranheim EA, Zhou Y, Zhou L, Kong G, Zhang J. Systemic Notch downregulation promotes KrasG12D-induced myeloproliferative neoplasm. Br J Haematol. 2019 Aug;186(3):e52-e56. doi: 10.1111/bjh.15893. Epub 2019 Mar 31.  PubMed PMID: 30931528.


Lu Z, Hong CC, Kong G, Assumpção ALFV, Ong IM, Bresnick EH, Zhang J, Pan X. Polycomb Group Protein YY1 Is an Essential Regulator of Hematopoietic Stem Cell Quiescence. Cell Rep. 2018 Feb 6;22(6):1545-1559. doi: 10.1016/j.celrep.2018.01.026. PubMed PMID: 29425509; PubMed Central PMCID: PMC6140794.

McIver SC, Hewitt KJ, Gao X, Mehta C, Zhang J, Bresnick EH. Dissecting Regulatory Mechanisms Using Mouse Fetal Liver-Derived Erythroid Cells. Methods Mol Biol. 2018;1698:67-89. doi: 10.1007/978-1-4939-7428-3_4. PubMed PMID: 29076084; PubMed Central PMCID: PMC5842797.

Peng Y, Shapiro SL, Banduseela VC, Dieterich IA, Hewitt KJ, Bresnick EH, Kong G, Zhang J, Schueler KL, Keller MP, Attie AD, Hacker TA, Sullivan R, Kielar-Grevstad E, Arriola Apelo SI, Lamming DW, Anderson RM, Puglielli L. Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging Cell. 2018 Oct;17(5):e12820. doi: 10.1111/acel.12820. Epub 2018 Jul 27. PubMed PMID: 30051577; PubMed Central PMCID: PMC6156544.

You X, Kong G, Ranheim EA, Yang D, Zhou Y, Zhang J. Unique dependence on Sos1 in Kras (G12D) -induced leukemogenesis. Blood. 2018 Dec 13;132(24):2575-2579. doi: 10.1182/blood-2018-09-874107. Epub 2018 Oct 30. PubMed PMID: 30377195; PubMed Central PMCID: PMC6293870.


Chang YI, Damnernsawad A, Kong G, You X, Wang D, Zhang J. The mystery of oncogenic KRAS: Lessons from studying its wild-type counter part. Small GTPases. 2017 Oct 2;8(4):233-236. doi: 10.1080/21541248.2016.1215656. Epub 2016 Jul 22. PubMed PMID: 27449543; PubMed Central PMCID: PMC5680677.

Chang YI, Kong G, Ranheim EA, Tu PS, Yu YS, Zhang J. Dnmt3a haploinsufficiency cooperates with oncogenic Kras to promote an early-onset T-cell acute lymphoblastic leukemia. Am J Transl Res. 2017 Mar 15;9(3):1326-1334. eCollection 2017. PubMed PMID: 28386358; PubMed Central PMCID: PMC5376023.

Pang Y, Deng C, Geng S, Weng J, Lai P, Liao P, Zeng L, Lu Z, Zhang J, Du X. Premature exhaustion of mesenchymal stromal cells from myelodysplastic syndrome patients. Am J Transl Res 2017 Jul 15;9(7):3462-3468. eCollection 2017. PubMed PMID: 28804562; PubMed Central PMCID: PMC5527260.

Zhang J, Kong G, Rajagopalan A, Lu L, Song J, Hussaini M, Zhang X, Ranheim EA, Liu Y, Wang J, Gao X, Chang YI, Johnson KD, Zhou Y, Yang D, Bhatnagar B, Lucas DM, Bresnick EH, Zhong X, Padron E, Zhang J. p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia. Blood. 2017 Jan 19;129(3):358-370. doi: 10.1182/blood-2016-06-719237. PubMed PMID: 27815262; PubMed Central PMCID: PMC5248933


Chen Y, Zheng Y, You X, Yu M, Fu G, Su X, Zhou F, Zhu W, Wu Z, Zhang J, Wen R, Wang D. Kras Is Critical for B Cell Lymphopoiesis. J Immunol. 2016 Feb 15; 196(4):1678-85. doi: 10.4049/jimmunol. 1502112. Epub 2016 Jan 15. PubMed PMID: 26773157. PubMed Central PMCID: PMC4744498

Damnernsawad A, Kong G, Wen Z, Liu Y, Rajagopalan A, You X, Wang J, Zhou Y, Ranheim EA, Luo HR, Chang Q, Zhang J. Kras is Required for Adult Hematopoiesis. Stem Cells. 2016 Jul;34(7):1859-71. doi: 10.1002/stem.2355. PubMed PMID: 26972179. PubMed Central PMCID: PMC5358545

Kong G, Chang YI, Damnernsawad A, You X, Du J, Ranheim EA, Lee W, Ryu MJ, Zhou Y, Xing Y, Chang Q, Burd CE, Zhang J. Loss of wild-type Kras promotes activation of all Ras isoforms in oncogenic Kras-induced leukemogenesis. Leukemia. 2016 Jul;30(7):1542-51. doi: 10.1038/leu.2016.40. PubMed PMID: 27055865; PubMed Central PMCID: PMC5316475.

Kong G, Chang YI, You X, Ranheim EA, Zhou Y, Burd CE, Zhang J. The ability of endogenous Nras oncogenes to initiate leukemia is codon-dependent. Leukemia. 2016 Sep;30(9):1935-8. doi: 10.1038/leu.2016.89. PubMed PMID: 27109513; PubMed Central PMCID: PMC5347394.


Chang YI, You X, Kong G, Ranheim EA, Wang J, Du J, Liu Y, Zhou Y, Ryu MJ, Zhang J. Loss of Dnmt3a and endogenous KrasG12D/+ cooperate to regulate hematopoietic stem and progenitor cell functions in leukemogenesis. Leukemia. 2015 Sep;29(9):1847-56. doi: 10.1038/leu.2015.85. Epub 2015 Mar 24. PubMed PMID:  25801914; PubMed Central PMCID: PMC4558337.

Johnson KD, Kong G, Gao X, Chang YI, Hewitt KJ, Sanalkumar R, Prathibha R, Ranheim RA, Dewey CN, Zhang J, Bresnick EH.  Cis-regulatory mechanisms governing stem and progenitor cell transitions. Sci Adv. 2015 Jun 20;1(8):e1500503. doi: 10.1126/sciadv.1500503. Epub 2015 Sept 4. PubMed PMID: 26601269; PubMed Central PMCID:  PMC4643771.

Liu Z, Morgan S, Ren J, Wang Q, Annis DS, Mosher DF, Zhang J, Sorenson CM, Sheibani N, Liu B. Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm. Circ Res. 2015 Jul 3;117(2):129-41. doi: 10.1161/CIRCRESAHA.117.305262. Epub 2015 May 4. PubMed PMID: 25940549; PubMed Central PMCID: PMC4490953.

Wang T, Li C, Xia C, Dong Y, Yang D, Geng Y, Cai J, Zhang J, Zhang X, Wang J. Oncogenic NRAS hyper-activates multiple pathways in human cord blood stem/progenitor cells and promotes myelomonocytic proliferation in vivo. Am J Transl Res. 2015 Oct 15;7(10):1963-73. eCollection 2015. PubMed PMID: 26692939; PubMed Central PMCID: PMC4656772.

Zhang J, Ranheim EA, Du J, Liu Y, Wang J, Kong G, Zhang J. Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in NrasG12D/+ Mice. J Biol Chem. 2015 Jul 31;290(31):19093-103. doi: 10.1074/jbc.M115.653154. Epub 2015 Jun 16. PubMed PMID: 26082490; PubMed Central PMCID: PMC4521033.


Chang, Y.-I., Damnernsawad, A., Allen, L. K., Yang, D., Ranheim, E. A., Young, K. H., Zhang, J., Kong, G., Wang, J., Liu, Y., Fu, H.-Y., Yang, C.-S., Guo, J., Song, H., and Zhang, J.  Evaluation of Allelic Strength of Human TET2 Mutations and Cooperation between Tet2 Knockdown and Oncogenic Nras Mutation.  Br. J. Haematol., 166(3): 461-465, 2014.

Kong, G., Wunderlich, M., Yang, D., Ranheim, E. A., Young, K. H., Wang, J., Chang, Y.-I., Du, J., Liu, Y., Tey, S. R., Zhang, X., Juckett, M., Mattison, R., Damnernsawad, A., Zhang, J., Mulloy, J. C., and Zhang, J.  Combined MEK and JAK Inhibition Abrogates Murine Myeloproliferative Neoplasm.  J. Clin. Invest., 124(6): 2762-2773, 2014.

Li, H., Zhong, X., Chau, K. F., Santistevan, N. J., Guo, W., Kong, G., Li, X., Kadakia, M., Masliah, J., Chi, J., Jin, P., Zhang, J., Zhao, X., and Chang, Q.  Cell Cycle-Linked MeCP2 Phosphorylation Modulates Adult Neurogenesis Involving the Notch Signaling Pathway.  Nat. Commun., 5:5601, 2014.

Sanalkumar, R., Johnson, K. D., Gao, X., Boyer, M. E., Chang, Y.-I., Hewitt, K. J., Zhang, J., and Bresnick, E. H.  Mechanism Governing a Stem Cell-Generating cis-Regulatory Element.  Proc. Natl. Acad. Sci. USA, 111(12):  E1091-E1100, 2014.


Anderson, S. A., Nizzi, C. P., Chang, Y.-I., Deck, K. M., Schmidt, P. J., Galy, B., Damnernsawad, A., Broman, A. T., Kendziorski, C., Hentze, M. W., Fleming, M. D., Zhang, J., and Eisenstein, R. S.  The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption.  Cell Metab., 17(2):  282-290, 2013.

Du, J., Liu, Y., Meline, B., Kong, G., Tan, L. X., Lo, J. C., Wang, J., Ranheim, E., Zhang, L., Chang, Y. I., Ryu, M. J., Zhang, J. F., and Zhang, J.  Loss of CD44 Attenuates Aberrant GM-CSF Signaling in Kras G12D Hematopoietic Progenitor/Precursor Cells and Prolongs the Survival of Diseased Animals.  Leukemia, 27(3): 754-757, 2013.

Gao, X., Johnson, K. D., Chang, Y.-I., Boyer, M. E., Dewey, C. N., Zhang, J., and Bresnick, E. H.  Gata2 cis-Element Is Required for Hematopoetic Stem Cell Generation in the Mammalian Embryo.  J. Exp. Med., 210(13): 2833-2842, 2013.

Kong, G., Du, J., Liu, Y., Meline, B., Chang, Y.-I., Ranheim, E. A., Wang, J., and Zhang, J.  Notch1 Gene Mutations Target KRAS G12D-expressing CD8+ Cells and Contribute to Their Leukemogenic Transformation.  J. Biol. Chem., 288(25): 18219-18227, 2013.

Wang, J., Kong, G., Liu, Y., Du, J., Chang, Y.-I., Tey, S. R., Zhang, X., Ranheim, E. A., Saba-El-Leil, M. K., Meloche, S., Damnernsawad, A., Zhang, J., and Zhang, J.  NrasG12D/+ Promotes Leukemogenesis by Aberrantly Regulating Hematopoietic Stem Cell Functions.  Blood, 121(26): 5203-5207, 2013.


Du, J., Wang, J., Kong, G., Jiang, J., Zhang, J., Liu, Y., Tong, W., and Zhang, J.  Signaling Profiling at the Single-Cell Level Identifies a Distinct Signaling Signature in Murine Hematopoietic Stem Cells.  Stem Cells, 30: 1447-1454, 2012.

Johnson, K. D., Hsu, A. P., Ryu, M.-J., Wang, J., Gao, X., Boyer, M. E., Liu, Y., Lee, Y., Calvo, K. R., Keles, S., Zhang, J., Holland, S. M., and Bresnick, E. H.  Cis-Element Mutated in GATA2-Dependent Immunodeficiency Governs Hematopoiesis and Vascular Integrity.  J. Clin. Invest., 122:  3692-3704, 2012.

Ryu, M.-J., Liu, Y., Zhong, X., Du, J., Peterson, N., Kong, G., Li, H., Wang, J., Salamat, S., Chang, Q., and Zhang, J.  Oncogenic Kras Expression in Postmitotic Neurons Leads to S100A8-S100A9 Protein Overexpression and Gliosis.  J. Biol. Chem., 287:  22948-22958, 2012.

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