Research Interest
- Molecular and cellular mechanisms of oncogenes and tumor suppressor genes in the development of leukemia
- Gene regulation
- Leukemic stem cell biology
- Basic and translational leukemia research
- Proteomics
The overall goal of my research program is to understand the molecular mechanisms of gene regulation and the cellular functions of oncogenes and tumor suppressor genes in the development of human leukemia. The ultimate objective is to identify molecules and pathways that will lead to new, rationally designed, more effective, and less toxic molecularly targeted therapies.
My research objectives are currently focused on delineating the normal functions and transforming properties of a novel oncogene, Ahi-1/AHI-1 (Abelson helper integration site 1). Ahi-1 is a recently identified gene that is commonly activated by provirus insertional mutagenesis, possibly in cooperation with other oncogenes (v-abl and Myc) or with a tumor suppressor gene (NF1), in different types of murine leukemias and lymphomas. Ahi-1 is unique in its possession of a SH3 domain, multiple SH3 binding sites and multiple WD40-repeat domains, suggesting that it has novel signaling activities. Interestingly, in leukemias involving Ahi-1 mutations, truncated Ahi-1/viral fused transcripts are produced, including splice variants in which the SH3 domain is deleted. We have recently demonstrated that Ahi-1/AHI-1 transcript levels are normally down-regulated during both early murine and human hematopoietic cell differentiation and are highly deregulated in human leukemic cells, particularly in highly enriched populations of BCR-ABL+ leukemic stem cells (lin-CD34+CD38-) from patients with chronic myeloid leukemia (CML) where levels of BCR-ABL transcripts are also elevated. We are now further characterizing the functions of Ahi-1 and its isoforms during normal mouse development and during early stages of normal hematopoietic cell differentiation and examining the biological changes of human AHI-1 and its isoforms in human leukemic stem/progenitors cells.
We have recently developed two important new models of BCR-ABL-mediated leukemia in mice. These allow the development of disease from a cell with stem cell properties to be followed over a period of 2-4 months, thus recreating a pathogenesis that more closely resembles the emergence of human chronic phase CML. Using these new models, we investigate the leukemogenic consequences of deregulated expression of different Ahi-1/AHI-1 isoforms alone and in concert with other oncogenes and tumor suppressor genes in the development of leukemia in vivo and the resulting altered factor-dependence or skewed or blocked ability to differentiate in vitro. The transforming properties of Ahi-1/AHI-1 are further evaluated by suppression of Ahi-1/AHI-1 (or other co-operating genes) expression in vitro and in vivo through virus-mediated RNA interference.
Another objective of my research is to understand the biological functions of Ahi-1/AHI-1 as a modular molecule that is likely to mediate specific protein-protein interactions to affect novel signaling pathways. Gene expression profiling and proteomic approaches have been applied to identify and characterize Ahi-1/AHI-1 interacting proteins involved in regulation of normal and leukemic stem/progenitor cell proliferation, self-renewal and differentiation.
Lab Group
Post-doc Position
We are currently accepting post-doctoral and graduate student applications.
Please submit a letter of interest with a CV by email to xjiang@bccrc.ca.