Jing Zhang
Assistant Professor
1995, Biochemistry and Molecular Biology, Beijing University, China
Postdoctoral Research: Whitehead Institute for Biomedical Research, Boston, MA
Lab Website: http://www.mcardle.wisc.edu/faculty/bio/zhang_j.html
Address: 417A McArdle Laboratory
Telephone: 263-1147
E-mail: Zhang@oncology.wisc.edu
Research Interests:
Hematopoietic stem cells; Leukemic stem cells; Mouse models for hematopoietic malignancies; Cytokine signaling
Research Fields:
Cancer Genetics
Developmental Genetics
Mouse Genetics
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
Representative Publications:
Wang,
J., Liu, Y., Tan, L. X., Lo, J. C., Du, J., Ryu, M.-J., Ranheim, R. A.,
and Zhang, J. Distinct requirements of hematopoietic stem cell activity
and Nras G12D signaling in different cell types during leukemogenesis. Cell
Cycle, in print, 2011.
Wang,
J., Liu, Y., Li, Z. Y., Wang, Z. D., Tan, L. X., Ryu, M.-J., Meline, B., Du,
J., Young, K.H., Ranheim, R. A., Chang, Q., and Zhang, J. Endogenous
oncogenic Nras signaling promotes hematopoietic malignancies in a dose- and
cell type-dependent manner. Blood, Epub May 17, 2011 ahead of print.
Wang,
J., Liu, Y., Li, Z. Y., Du, J., Ryu, M.-J., Fleming, M.D., Young, K.H., Pitot,
H.C., and Zhang, J. Endogenous Oncogenic Nras Mutation Promotes Aberrant
GM-CSF Signaling in Granulocytic/Monocytic Precursors in a Murine Model of
Chronic Myelomonocytic Leukemia. Blood, 116 (26): 5991-6002, 2010.
Zhang,
J., Lee, E. Y., Liu, Y. G., Berman, S. D., Lodish, H. F., and Lees, J. A.
pRB and E2F4 Play Distinct and Cell-Intrinsic Roles in Fetal
Erythropoiesis. Cell Cycle, 9(2): 371-376, 2010.
Lodish,
H. F., Ghaffari, S., Socolovsky, M., Tong, W., and Zhang, J.
Intracellular Signaling by the Erythropoietin Receptor. In: G.
Molineux, M. Foote, and S. Elliott (Eds.), Erythropoietins, Erythropoietic
Factors and Erythropoiesis (MDT). Basel: Birkhauser Publ., 2009.
Zhang,
J.*, Wang, J., Liu, Y., Sidik, H., Young, K. H., Lodish, H. F., and Fleming, M.
D. Oncogenic Kras-induced Leukemogenesis: Hematopoietic Stem Cells
as the Initial Target and Lineage-specific Progenitors as the Potential Targets
for Final Leukemic Transformation. Blood, 113: 1304-1314, 2009.
Zhang, J., and Lodish, H. F. Endogenous K-ras signaling in erythroid differentiation. Cell Cycle 6(16):1970-1973, 2007.
Zhang, J., Liu, Y.G., Beard, C., Tuveson, D., Jaenisch, R., Jacks, T., and Lodish, H.F. Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways. Blood 109: 5238-5241, 2007.
Zhang, J., and Lodish, H.F. Identification of K-ras as the major regulator for cytokine-dependent Akt activation in erythropoiesis in vivo. PNAS 102 (41):14605-10, 2005.
Zhang, J., and Lodish, H.F. Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 104(6): 1679-1687, 2004.
Zhang, J., Socolovsky, M., Gross, A.W., and Lodish, H.F. Role of Ras signaling in erythoid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood 102(12): 3938-3946, 2003.
Assistant Professor
1995, Biochemistry and Molecular Biology, Beijing University, China
Postdoctoral Research: Whitehead Institute for Biomedical Research, Boston, MA
Address: 417A McArdle Laboratory
Telephone: 263-1147
E-mail: Zhang@oncology.wisc.edu
Research Interests:
Hematopoietic stem cells; Leukemic stem cells; Mouse models for hematopoietic malignancies; Cytokine signaling
Research Fields:
Cancer Genetics
Developmental Genetics
Mouse Genetics
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
Wang, J., Liu, Y., Tan, L. X., Lo, J. C., Du, J., Ryu, M.-J., Ranheim, R. A., and Zhang, J. Distinct requirements of hematopoietic stem cell activity and Nras G12D signaling in different cell types during leukemogenesis. Cell Cycle, in print, 2011.
Wang, J., Liu, Y., Li, Z. Y., Wang, Z. D., Tan, L. X., Ryu, M.-J., Meline, B., Du, J., Young, K.H., Ranheim, R. A., Chang, Q., and Zhang, J. Endogenous oncogenic Nras signaling promotes hematopoietic malignancies in a dose- and cell type-dependent manner. Blood, Epub May 17, 2011 ahead of print.
Wang, J., Liu, Y., Li, Z. Y., Du, J., Ryu, M.-J., Fleming, M.D., Young, K.H., Pitot, H.C., and Zhang, J. Endogenous Oncogenic Nras Mutation Promotes Aberrant GM-CSF Signaling in Granulocytic/Monocytic Precursors in a Murine Model of Chronic Myelomonocytic Leukemia. Blood, 116 (26): 5991-6002, 2010.
Zhang, J., Lee, E. Y., Liu, Y. G., Berman, S. D., Lodish, H. F., and Lees, J. A. pRB and E2F4 Play Distinct and Cell-Intrinsic Roles in Fetal Erythropoiesis. Cell Cycle, 9(2): 371-376, 2010.
Lodish, H. F., Ghaffari, S., Socolovsky, M., Tong, W., and Zhang, J. Intracellular Signaling by the Erythropoietin Receptor. In: G. Molineux, M. Foote, and S. Elliott (Eds.), Erythropoietins, Erythropoietic Factors and Erythropoiesis (MDT). Basel: Birkhauser Publ., 2009.
Zhang, J.*, Wang, J., Liu, Y., Sidik, H., Young, K. H., Lodish, H. F., and Fleming, M. D. Oncogenic Kras-induced Leukemogenesis: Hematopoietic Stem Cells as the Initial Target and Lineage-specific Progenitors as the Potential Targets for Final Leukemic Transformation. Blood, 113: 1304-1314, 2009.
Zhang, J., and Lodish, H. F. Endogenous K-ras signaling in erythroid differentiation. Cell Cycle 6(16):1970-1973, 2007.Zhang, J., Liu, Y.G., Beard, C., Tuveson, D., Jaenisch, R., Jacks, T., and Lodish, H.F. Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways. Blood 109: 5238-5241, 2007.
Zhang, J., and Lodish, H.F. Identification of K-ras as the major regulator for cytokine-dependent Akt activation in erythropoiesis in vivo. PNAS 102 (41):14605-10, 2005.
Zhang, J., and Lodish, H.F. Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 104(6): 1679-1687, 2004.
Zhang, J., Socolovsky, M., Gross, A.W., and Lodish, H.F. Role of Ras signaling in erythoid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood 102(12): 3938-3946, 2003.
