Jerald P. Radich
M.D., University of California School of Medicine - Davis, 1983.
Molecular genetics of leukemia and the detection of minimal residual disease.
We are studying the molecular genetics of response, progression, and relapse in human leukemia. These studies rely on a close interaction of our lab to clinical research performed at the Center, as well as collaborations with large clinical trials of the Southwest Oncology Group. Our work falls into three major categories:
1.The detection of minimal residual disease. The major obstacle to curing leukemia is relapse. Unfortunately, the conventional definition of remission is inadequate, as many patients deemed to be in remission nonetheless eventually relapse. Could we cure more patients if we could identify which patients harbored minimal residual disease (MRD) and treat those patients earlier, before frank relapse? We use highly sensitive molecular techniques, such as the polymerase chain reaction (PCR), to identify the molecular fingerprints of leukemia, and then detect these fingerprints during remission, testing ifMRD indeed predicts relapse. We have previously demonstrated that the detection of leukemia-specific fingerprints in patients with chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) was strongly associated with subsequent relapse. Studies are ongoing to examine the clinical significance of MRD detection in ALL, CML, and acute myeloid leukemia (AML).
2. Signal transduction abnormalities in leukemia. We are using AML as a model to examine the molecular genetics of leukemogenesis, andto map the association of specific genetic aberrations with response and outcome. We are first trying to dissect the involvement of a number of genes in the ras signalling pathway, as well as perturbations of tumor suppressors causing dysfunction of theapoptotic pathway. We are especially interested in mutations of the tyrosine kinase Flt3, which appear to be quite common in AML, and carry a poor prognosis.
3. Gene expression profiles of response and progression. We are using CML as a model diseaseto study the biology of progression and response using microarray gene expression analysis. CML has the distinct feature of beginning in a chronic phase which invariably evolves to a highly aggressive blast crisis. The genes involved in this stereotyped progression are unknown. We are using the newly evolving microarray chip systems to simultaneously examine the expression patterns of thousands of genes during the progression of CML. In addition, we are using this technology to examine the gene expression patterns associated with interferon response in CML. Future studies will likely include the examination of gene expression patterns that predict response in ALL and AML.
Sequencing small genomic targets with high efficiency and extreme accuracy.. Nature methods. 12(5):423-5.. 2015.
Treatment milestones in chronic myelogenous leukemia: stay the course or change therapy? Journal of the National Comprehensive Cancer Network : JNCCN. 13(5 Suppl):697-9.. 2015.
Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 33(10):1157-64.. 2015.
Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia.. Science translational medicine. 7(281):281re2.. 2015.
Chronic myelogenous leukemia, version 1.2015.. Journal of the National Comprehensive Cancer Network : JNCCN. 12(11):1590-610.. 2014.
Monitoring molecular response to tyrosine kinase therapy in chronic myelogenous leukemia.. Journal of the National Comprehensive Cancer Network : JNCCN. 12(5 Suppl):817-20.. 2014.
JAK Inhibitors and Allogeneic Stem Cell Transplantation for Myelofibrosis.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2014.
Integrating current treatment options for TKI-resistant chronic myeloid leukemia.. Clinical advances in hematology & oncology : H&O. 12(7 Suppl 13):3-17,1.. 2014.
Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia.. Leukemia research. 38(1):10-20.. 2014.
Self-digitization microfluidic chip for absolute quantification of mRNA in single cells.. Analytical chemistry. 86(24):12308-14.. 2014.
Impact of minimal residual disease, detected by flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia.. Leukemia research and treatment. 2014:421723.. 2014.
Chronic Myelogenous Leukemia, Version 1.2014.. Journal of the National Comprehensive Cancer Network : JNCCN. 11(11):1327-40.. 2013.
The Role of Transplant in CML.. Clinical advances in hematology & oncology : H&O. 11(11 Suppl 17):11-2.. 2013.
Sequential therapy in chronic myelogenous leukemia: general discussion.. Clinical advances in hematology & oncology : H&O. 11(11 Suppl 17):13-4.. 2013.
Monitoring response to tyrosine kinase inhibitor therapy, mutational analysis, and new treatment options in chronic myelogenous leukemia.. Journal of the National Comprehensive Cancer Network : JNCCN. 11(5 Suppl):663-6.. 2013.
Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients.. Science translational medicine. 5(174):174ra27.. 2013.
European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.. Blood. 122(6):872-84.. 2013.