Biomedical subjects
Publications and source records attributed to Louis M Staudt.
The molecular diagnosis of human cancer will hasten the development of treatments tailored to the abnormalities present in each patient's tumor cells. Recent gene expression profiling studies of pediatric acute lymphoblastic leukemia (ALL) suggest that the molecular diagnosis of these diseases is right around the corner.
When the regulation of B-cell differentiation and activation is disrupted, lymphomas and leukaemias can occur. The processes that normally create immunoglobulin diversity might be misdirected, resulting in oncogenic chromosomal translocations that block differentiation, prevent apoptosis and/or promote proliferation. Prolonged or unregulated antigenic stimulation might contribute further to the development and progression of some malignancies. Lymphoid malignancies often resemble normal stages of B-cell differentiation, as shown by molecular techniques such as gene-expression profiling. The similarities and differences between malignant and normal B cells indicate strategies for the treatment of these cancers.
Current lymphoma classification schemes that incorporate information on immunophenotype and genetic aberrations of the neoplastic cells represent a first attempt at a molecular diagnosis of these malignancies. Gene expression profiling using DNA microarrays promises to dramatically enhance molecular diagnosis by quantitating gene expression in tumor cells on a genomic scale. In this review, we focus on recent studies of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) that illustrate the effectiveness of gene expression profiling in defining molecularly distinct diseases. In DLBCL, germinal center B-like (GCB) and activated B-cell-like (ABC) subgroups differ in the expression of more than 1,000 genes and have a markedly different clinical outcome, suggesting that this diagnostic category includes at least two distinct molecular diseases. In CLL, by contrast, all cases express a characteristic set of genes, suggesting that CLL should be considered a single disease. Nonetheless, two subtypes of CLL exist that are distinguished by the presence or absence of immunoglobulin gene mutations, by the expression of approximately 175 genes, and by clinical course. Clinical translation of these results should be implemented initially in clinical trials where gene expression profiles could identify subsets of patients that are particularly responsive to the therapies being evaluated. As the armamentarium of molecularly targeted therapies expands, molecular diagnosis will be seen as an integral component of clinical management.
Gene expression profiling using DNA microarrays has great potential to improve the understanding, diagnosis, and management of lymphomas, leukemias, and other malignancies. Gene expression profiling studies of diffuse large B-cell lymphoma (DLBCL) have shown that this diagnostic category encompasses at least two molecularly distinct diseases, differing in differentiation stage (cell of origin), oncogenic mechanisms, and clinical outcome. Gene expression profiling revealed that the antiapoptotic NF-kappaB pathway is constitutively active in one DLBCL subgroup, termed activated B cell-like DLBCL, and subsequent studies validated NF-kappaB as a therapeutic target in this type of lymphoma. DNA microarray studies of chronic lymphocytic leukemia (CLL) have led to a gene expression-based predictor that identifies two subtypes of CLL that differ with respect to clinical course and presence of immunoglobulin gene mutations in the CLL cells. These findings underscore the value of gene expression profiling in defining subtypes within the lymphoid malignancies that are molecularly and clinically distinct and argue that this genomic technology should become an integral part of prospective clinical trials.
Comprehensive gene expression profiling using DNA microarrays is providing a molecular classification of cancer into disease categories that are homogeneous with respect to pathogenesis and clinical behavior. Gene expression profiling revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two molecularly distinct diseases that are derived from distinct stages of B cell differentiation and have strikingly different clinical outcomes. By contrast, chronic lymphocytic leukemia (CLL) was found to be a single disease defined by a characteristic gene expression signature. Nonetheless, gene expression profiling distinguished two clinically divergent CLL subtypes and provided evidence that signaling through the B cell antigen receptor may play a role in the clinically aggressive subtype. Gene expression analysis also illuminated the mechanism of lymphomagenesis caused by BCL-6 translocations and provided evidence that the NF-kappa B signaling pathway is a new molecular therapeutic target in DLBCL.