Zhe Li

Department of Medicine

Division of Genetics
Brigham and Women's Hospital
New Research Building, Room 466B
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 525-4740
Fax: (617) 525-4705
Email: zli4@rics.bwh.harvard.edu

The broad interest of Li laboratory is stem cells and cancer. We are particularly interested in understanding how cancer stem cells (CSCs, also known as tumor-initiating cells, or tumor-propagating cells) evolve from normal target cells of cancer through accumulation of mutations and through interaction with microenvironments, as avenues for identifying pathways unique to them. We are also interested in exploring how CSCs can be instructed to differentiate. We study these by applying concepts and tools from stem cell biology and developmental biology, and by using a combination of mouse genetics, biochemistry, and genomic approaches. The long-term goal is to develop novel therapeutic approaches targeting CSCs. Current projects in our laboratory include:

Breast cancer stem cells and their cellular origins: We recently generated a novel mouse model of human breast cancer initiated by the t(12;15) ETV6-NTRK3 chromosomal translocation. It provides a unique opportunity to identify the affected population of cells early in the evolution of cancer. Currently, we are using this model to identify and characterize genetically marked target cells of cancer, premalignant cells, and CSCs. By flow cytometry and genomic approaches, we will identify additional mutations and deregulated pathways leading to the formation of CSCs, and validate them in mouse models.

ERG in stem cells and cancer: ERG is an ETS family transcription factor playing critical roles in both normal development (e.g., in hematopoietic stem cells) and disease, particularly in prostate cancer. It is overexpressed in >50% of human prostate cancer cases due to TMPRSS2-ERG gene fusions. Many of these fusions are generated through an intrachromosomal deletion between TMPRSS2 and ERG. We are using knockin mouse models to study roles of ERG as well as genes deleted between Tmprss2 and Erg to prostate tumorigenesis. We are also using conditional approaches to study the role of Erg in normal and malignant stem cells in mice.

miR-125b in hematopoiesis and leukemogenesis: miR-125b is a microRNA overexpressed in Down syndrome acute megakaryoblastic leukemia (DS-AMKL). We recently identified this microRNA as a potential oncomiR directly contributes to DS-AMKL. We are currently investigating how it contributes to leukemia and how genes encoding it are regulated in hematopoietic cells.

Transcription network in epithelial cells: We are developing a new project to explore the transcription network in epithelial cells and understand how perturbation of the network contributes to cancer. We will use a metabolic biotin tagging system, coupled with mass spectrometry and ChIP analysis, to study this. Currently, we are establishing a GATA3-centered transcription network in breast cancer cells.

References:

Klusmann JH, Godinho FJ, Heitmann K, Maroz A, Koch ML, Reinhardt D, Orkin SH, Li Z. Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. Genes Dev.

2010;24(15):1659-72.
Klusmann J-H*, Li Z*, Böhmer K, Maroz A, Koch ML, Emmrich S, Godhinho FJ, Orkin SH, Reinhardt D. miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. Genes Dev. 2010;24(5):478-90. (*co-first author)
Li Z, Tognon CE, Godinho FJ, Yasaitis L, Hock H, Herschkowitz JI, Lannon CL, Cho E, Kim S-J, Bronson RT, Perou CM, Sorensen PH, Orkin SH. ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex. Cancer Cell. 2007;12(6):542-58.
Li Z*, Chen MJ*, Stacy T, Speck NA. Runx1 function in hematopoiesis is required in cells that express Tek. Blood. 2006;107(1):106-10. (*co-first author)
Li Z, Godinho FJ, Klusmann J-H, Garriga-Canut M, Yu C, Orkin SH. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor – GATA1. Nat Genet. 2005;37(6):613-9.

BBS webpage updated 5/19/2010