Our laboratory studies the molecular pathogenesis of human lymphoid malignancies and has three primary goals: to establish a new molecular diagnosis of human lymphoid malignancies using gene expression profiling, to elucidate the oncogenic pathways that result in malignant transformation of normal B lymphocytes, and to identify molecular targets for development of novel therapeutics for these cancers. To provide a molecular basis for the diagnosis of human lymphoid malignancies, we are exploiting DNA microarray technology to profile gene expression in these cancers on a genomic scale. The laboratory created a novel DNA microarray, the 'Lymphochip', which is enriched in genes that are expressed in and/or function in lymphocytes. We have used Lymphochip and Affymetrix microarrays to profile gene expression in diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma, follicular lymphoma, Burkitt lymphoma, multiple myeloma, and in a wide variety of normal lymphoid subsets. One central goal of these studies is to relate gene expression to clinical outcome, thereby establishing a quantitative, reproducible and informative molecular diagnosis of the lymphoid malignancies. Our studies have revealed previously unknown types of diffuse large B cell lymphoma that are indistinguishable by current diagnostic methods, but which have strikingly distinct gene expression profiles, originate from different stages of B cell differentiation, utilize distinct oncogenic mechanisms, and differ in their ability to be cured by current chemotherapy. For several lymphoid malignancies, we have identified molecular profiles that predict the length of survival or the ability to be cured by chemotherapy, thereby providing clinically useful prognostic indicators. Our laboratory has mounted a major effort to create a diagnostic microarray that could provide these molecular diagnoses and prognoses to patients with lymphoid malignancies. The importance of this initiative is that current methods used in the diagnosis of lymphoid malignancies are imprecise, leading to misdiagnosis in a fraction of cases. For example, Burkitt lymphoma was incorrectly diagnosed as DLBCL using current pathology techniques in roughly one sixth of cases. Since different chemotherapeutic regimens are required to cure this two lymphoma types, diagnostic accuracy is crucial, and may be best accomplished by gene expression profiling. Our laboratory uses functional genomics, chemical genetics and molecular biological techniques to identify new molecular targets for therapy of lymphoid malignancies. Some of the genes that are associated with clinical prognosis have provided new molecular targets. For example, our laboratory discovered that the subgroup of DLBCL with the worst prognosis relies on constitutive activity of the NF-kB signaling pathway for survival; molecular or pharmacological inhibition of this pathway kills this type of lymphoma. Likewise, we found that the NF-kB pathway is constitutively activated by diverse genetic abnormalities in a subset of multiple myeloma cases, and this makes these myelomas sensitive to NF-kB pathway inhibition. A major new initiative aims to identify molecular targets in lymphoid malignancies using large scale RNA interference. The laboratory has created a library of over 10,000 retroviruses that can inducibly express small hairpin RNAs (shRNAs) targeting more than 3,000 human genes. When expressed in a cell, each shRNA can be processed into a small interfering RNA that can decrease the mRNA expression of a single human gene. We are using this library to identify genes that are important for the proliferation and survival of lymphoma and myeloma cells. This approach uncovered the CARD11/BCL10/MALT1 pathway as responsible for the constitutive NF-kB activation in a subtype of DLBCL.
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