The assessment of remission in the treatment of leukemia provides the strongest measure of therapeutic outcome and prognostication. However, with the exception of chronic myelogenous leukemia (CML), our ability to measure this important parameter is limited by current technology to at best 1 to 5% leukemic cells in a background of normal cells. We plan to use the Polymerase Chain Reaction (PCR) to amplify specific DNA sequences of Acute Lymphocytic (ALL) and Acute Myelogenous Leukemia (AML) cells which can be used to detect minimal residual disease (MRD). In ALL, we will use the unique nucleotide sequences caused by immunoglobulin heavy chain (in B cells) or T cell receptor gamma (in T cells) gene rearrangement as a """"""""fingerprint"""""""" of the malignant clone, in AML we will use the point mutation of the N-ras oncogene as the leukemia-specific marker. We hope to develop a practical and reliable laboratory approach capable of detecting leukemic MRD at a level of at least one leukemic cell per 10,000 normal cells or better. To test the clinical relevance of these protocols, samples from patients with stored bone marrows from diagnosis and remission will be tested for MRD; since these patients have substantial follow-up (greater than 2 years), we should be able to test if the detection of MRD predicts outcome during this period of high relapse risk. The ability to detect MRD may provide a more rigorous and clinically relevant definition of remission which could potentially aid clinicians in estimating prognosis, choosing proper therapeutic options, and evaluating the efficacy of treatment modalities. Moreover, this methodology may serve as a model system for detecting MRD in other potentially curable malignancies where relapse is problematic, such as lymphoma, ovarian, and breast cancer. The candidate's interest is in bringing the scientific and technical developments of molecular biology into the arena of clinical medicine. His past studies have dealt with the prevalence and significance of N-ras point mutations in CML and AML; these studies have afforded him an understanding of many molecular biology techniques, especially PCR and sequencing. This proposal would further his development into a clinical scientist. The environment of this study would be especially suitable to this end. The Fred Hutchinson Cancer Research Center offers a unique supply and mix of clinical cases together with numerous research scientists practicing state-of-the-art molecular biology. In Dr. Steven Collins, the candidate has a mentor recognized as a solid and successful scientist as well as a skilled clinician. In sum, this proposal could broaden the understanding of the biology of leukemia, aid in its therapy, and provide support to an emerging clinical scientific career.
| Radich, J; Gehly, G; Lee, A et al. (1997) Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood 89:2602-9 |
| Radich, J; Ladne, P; Gooley, T (1995) Polymerase chain reaction-based detection of minimal residual disease in acute lymphoblastic leukemia predicts relapse after allogeneic BMT. Biol Blood Marrow Transplant 1:24-31 |
