Christopher Hsu

Current Research Interests

Acute myeloid leukemia (AML) is a malignancy consisting of a heterogeneous population of cells with differing leukemic potential. Though AML has achieved a cure rate of almost 80%, a significant number of patients relapse with dismal post-relapse survival of 30%. Explaining how different leukemic cells manifest as cancer and why certain patients respond poorly to therapy has been debated among research groups. The theory that leukemic stem cells, self-replicating clones with the potential to mature into any mature lineage, are the source of all leukemia has been hotly disputed as an explanation. Current evidence has shown that leukemia is possibly arranged in an hierarchical fashion with the pinnacle dominated by a leukemic stem cell. If leukemic stem cells are truly the source of leukemic disease the question is what truly occurs to these leukemic stem cells clones and their differentiated progeny during therapy. Furthermore, it is understood that cancerous clones with stem cell-like properties appear to be more resistant to chemotherapy. One could infer from these findings that relapse is caused by selection of chemo-resistant leukemic stem cell clones; however, it is unclear whether these clones were present prior to chemotherapy, developed resistance during chemotherapy and if they are truly leukemic stem cells. Answering these difficult inquiries would require monitoring a vast number of cancer cells in order for one to observe the clonal dynamics of leukemic populations in the presence of chemotherapeutic agents.
We have a powerful tool in our laboratory, known as the molecular barcode, to help answer these very questions and to elucidate how relapse may occur. The barcode technology allows me to label the genomes of 20,000 individual AML cells each with a unique 20-basepair identifier using a lentivirus vector and thus track individual cells by second generation PCR. By tracking each cell in in vitro and in vivo mouse models I can determine if clones are selected in the presence of chemotherapy with the hope of clarifying the clonal dynamics of AML during and after chemotherapy. Fluorescence in situ hybridization, comparative genome hybridization analysis, micro-array analysis and deep sequencing will then characterize these unique clones for karyotypic or specific gene mutations that may potentially confer chemo-resistance. Furthermore, clones will also be assessed for leukemic stem cell features. This project will be conducted on established AML cell lines and on samples from patients who have relapsed or have developed secondary leukemia. Identifying and studying the molecular characteristics of these clones may help broaden understanding of how chemo-resistance occur, explain why relapse occurs in certain individuals and not others and potentially lead to more effective AML treatments.