Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features, presenting as a relatively clinically benign state ( chronic phase ), which invariably evolves to an incurable aggressive disease ( blast crisis ). Treatment can range from low intensity chemotherapy to the curative yet potentially lethal therapy of bone marrow transplantation (BMT). Unfortunately little is known about the molecular events that trigger the evolution of chronic phase to blast crisis. Thus, tailoring therapy to individual patient s risk is impossible. This proposal aims to identify changes in gene expression that occur in the evolution of the chronic phase to blase crisis, as well as discovering gene expression patterns that are associated with good outcomes to conventional interferon-based therapy. Specifically, we will: 1) optimize and validate the expression array technology, then 2) use mRNA expression arrays to identify genes involved in the progression of chronic phase to blast phase CML; and 3) identify genes associated with good or poor outcome following conventional interferon-based therapy. These studies will allow us to begin to study the biology of CML transformation, and understand at a genetic level why some patients respond to conventional therapy, while other patients are refractory to therapy, and quickly transform to highly aggressive disease. The identification of low v high risk patients will allow theraphy to be appropriately tailored to each individual s disease. In addition, the application of large-scale expression analysis in this model system will be ideal to iron out unforeseen technical problems, and thus the experience gained may be very valuable in future investigations other more complex tumor systems.
|Hoshino, Koyu; Quintás-Cardama, Alfonso; Radich, Jerald et al. (2009) Downregulation of JUNB mRNA expression in advanced phase chronic myelogenous leukemia. Leuk Res 33:1361-6|
|Bellido, Mar; Stirewalt, Derek L; Zhao, Lue Ping et al. (2006) Use of gene expression microarrays for the study of acute leukemia. Expert Rev Mol Diagn 6:733-47|
|Radich, Jerald P; Dai, Hongyue; Mao, Mao et al. (2006) Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 103:2794-9|
|Stirewalt, Derek L; Pogosova-Agadjanyan, Era L; Khalid, Najma et al. (2004) Single-stranded linear amplification protocol results in reproducible and reliable microarray data from nanogram amounts of starting RNA. Genomics 83:321-31|
|Radich, Jerald P; Mao, Mao; Stepaniants, Sergey et al. (2004) Individual-specific variation of gene expression in peripheral blood leukocytes. Genomics 83:980-8|
|Radich, Jerald P (2002) The promise of gene expression analysis in hematopoetic malignancies. Biochim Biophys Acta 1602:88-95|