By Mary Jo Lechowicz, MD
2009-12-06
The Role of Genomics in the Diagnosis, Prognosis, and Treatment of Lymphoid Malignancies” may hold the key to individualized therapy for patients. Today’s Scientific Program Session on advances in the genomics of lymphoid neoplasia will review the progress the field has made and how subtleties in clinical presentation are being explained biologically. This session is taking place again today at 9:30 a.m. in rooms 265-268 of the Ernest N. Morial Convention Center.
Dr. Adrian Wiestner of the National Heart, Lung, and Blood Institute of the National Institutes of Health in Bethesda has previously published data of his group’s investigations describing mantle-cell lymphoma (MCL) and how cyclin D1 gene (CCND1) expression may predict clinical outcomes of patients with these lymphomas. The group found that patients with high proliferation rate in MCL had mutations in the CCND1 3’-untranslated region (UTR). These mutations can significantly increase tumor proliferation and worsen the clinical course for patients with MCL.
Dr. Wiestner’s group has also used gene expression profiling to establish a “proliferation signature,” which can be the basis for individual therapeutic intervention. The NCI group is exploring this genomic profiling in their current clinical trial in leukemic phase mantle-cell lymphoma patients being treated with R-EPOCH. The results will be presented in an abstract by Weniger on Monday afternoon.
Dr. Charles Mullighan of the St. Jude Children’s Research Hospital in Memphis, TN, discussed how genomic profiling has provided important insights into the genetic lesions contributing to leukemogenesis. Novel genetic markers that predict risk of relapse in B-progenitor ALL, including IKZF1 (IKAROS) and others, have been identified. This information provides a new framework for targeted therapy in high-risk B-progenitor ALL. This latter work centers on studies published in PNAS and more recently in Nature Genetics, where Dr. Mullighan’s group identified a cohort of B-ALL cases that have poorer outcome. The studies identified mutations in JAK kinases and a novel rearrangement of a lymphoid cytokine receptor gene, CRLF2, in these cases. The JAK/CRLF2 translocation placed into cell lines in vitro leads to proliferation of these cells. JAK2 inhibition could be a mechanism of treatment of B-ALL. Dr. Mullighan also discussed the use of RNA-sequencing to profile genetic alterations in high-risk B-ALL, which may be more commonly used in the future. He will allude to additional newly identified translocations in B-ALL that will be presented on Monday.
Dr. Sami Malek of the University of Michigan at Ann Arbor will then describe the many genomic aberrations in CLL and how they can substantially contribute to the biology and clinical outcome in CLL. The 11q deletion (del11q) is just one of the chromosomal rearrangments known to shorten survival in patients with CLL. In about 30 percent of cases, 11q deletion is associated with ATM mutations on the retained chromosome; however, the altered ATM activity is not enough to explain the entire deletion 11q biology. Del11q is associated with compound defects in the DNA double-stranded break response. CLL cases with del11q express high levels of the insulin receptor, which may act as a proliferative or anti-apoptotic factor in CLL.
Deletion of chromosome 17q is also known to reduce survival in CLL. This deletion is associated with p53 dysfunction. P53 dysfunction and other genomic aberrations have been incorporated into a prospective assessment of biomarkers as predictors of disease progression and survival in CLL. Biomarker assessment will then allow for more informed treatment choices.
This exciting session gives hope for more individualized therapy for patients with lymphoid malignancies based on genomic signaling in the near future.
Dr. Lechowicz indicated no relevant conflicts of interest.
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