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.
Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients.. Science translational medicine. 5(174):174ra27.. 2013.
Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia.. Cancer. 118(2):300-11.. 2012.
Chronic myeloid leukemia 2011: Successes, challenges, and strategies-Proceedings of the 5th annual BCR-ABL1 positive and BCR-ABL1 negative myeloproliferative neoplasms workshop.. American journal of hematology. 86(9):811-9.. 2011.
The biology of chronic myelogenous leukemia progression: who, what, where, and why? Hematology/oncology clinics of North America. 25(5):967-80.. 2011.
BCR-ABL Transcript Dynamics Support the Hypothesis That Leukemic Stem Cells Are Reduced during Imatinib Treatment.. Clinical cancer research : an official journal of the American Association for Cancer Research. 17(21):6812-6821.. 2011.
Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and comorbidities.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 17(6):908-15.. 2011.
Stem cell transplant for chronic myeloid leukemia in the imatinib era.. Seminars in hematology. 47(4):354-61.. 2010.
Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 24(5):909-13.. 2010.
The molecular biology of myeloproliferative disorders.. Cancer cell. 18(1):7-8.. 2010.
Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia.. British journal of haematology. 151(5):430-4.. 2010.
Regulation of myeloid leukaemia by the cell-fate determinant Musashi.. Nature. 466(7307):765-8.. 2010.
Chronic myeloid leukemia 2010: where are we now and where can we go? Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2010:122-8.. 2010.
Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 27(25):4204-10.. 2009.