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Addiction to an Aberrant Network: IRF4 in Multiple Myeloma

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Air date: Wednesday, May 28, 2008, 4:15:00 PM
Time displayed is Eastern Time, Washington DC Local
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Category: Immunology
Runtime: 00:57:00
Description: Dr. Shaffer has a fundamental interest in the application of basic immunology to problems involving the dysregulation of the immune system, especially with regard to cancer. He developed his abiding interest in basic immunology as a graduate student at Johns Hopkins under the tutelage of then new faculty member Mark Schlissel, studying the targeting and timing of V(D)J recombination during early B cell development.

Continuing to pursue his interest in understanding the interplay of normal and pathological immune system development, Dr. Shaffer became a post-doctoral fellow in the laboratory of Dr. Louis Staudt in the National Cancer Institute in 1996. His first effort was to uncover the genes lying downstream of a transcriptional repressor, BCL6, which is not only essential for normal germinal B cell differentiation but is also a target of recurrent translocations in diffuse large B cell lymphoma, a malignancy of germinal center B cells. Employing the then-novel technology of gene expression microarrays developed in the Staudt lab, Dr. Shaffer found that BCL6 represses genes involved in B cell activation, inflammation, and terminal plasmacytic differentiation, thereby enforcing the germinal center B cell program. Dr. Shaffer made a fundamental insight into the pathogenesis of diffuse large B cell lymphoma by demonstrating that BCL-6 represses Blimp-1, an essential regulator of plasmacytic differentiation. Normally, BCL-6 is silenced during plasmacytic differentiation, but translocations in diffuse large B cell lymphoma prevent this. BCL-6 expression in these lymphomas blocks Blimp-1, thereby trapping the malignant B cells at an intermediate stage of differentiation, halfway between the germinal center B cell and the plasma cell. Such diffuse large B cell lymphomas, known as the activated B cell-like (ABC) subtype, have a plasmablastic phenotype, express AID highly, and accumulate a variety of other cooperating oncogenic mutations.

After this initial success in combining gene expression profiling and the study of B cell differentiation, Dr. Shaffer went on to elucidate the action of several additional critical B cell differentiation-related transcription factors. His work, along with the efforts of many excellent collaborators has shown that: - the critical plasma cell transcriptional repressor, Blimp-1, shuts down the B cell gene expression program and forms a negative feedback loop with BCL6 to lock cells into a terminally differentiated state. - the plasma cell transcriptional activator, XBP1, is a master regulator of the secretory system and, surprisingly, also increases cell size and protein translation, allowing for maximal antibody synthesis. - the transcription factor IRF4 coordinates B cell isotype switching and initiates plasma cell differentiation by inducing critical regulators of these processes, including AID and Blimp-1.

As a result of these experimental successes as a post-doc, Dr. Shaffer was appointed as a Staff Scientist in 2001, and has enjoyed connecting with the broader NIH immunology community through the Immunology Interest Group and the late, lamented B cell Workshop. He remains fundamentally convinced of the pre-eminence of the alphabetically superior lymphocyte.

In today’s lecture, Dr. Shaffer will illustrate how another genomic-scale technology, the Achilles’ heel RNA interference genetic screen, has revealed the pathological role of B cell-specific transcription factors in multiple myeloma, a malignancy of plasma cells. These observations exemplify a new notion in cancer biology, termed non-oncogene addiction.

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The Immunology Interest Group
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NLM Title: Addiction to an aberrant network : IRF4 in multiple myeloma [electronic resource] / Art Shafer.
Author: Shafer, Art.
National Institutes of Health (U.S.). Immunology Interest Group.
Publisher:
Abstract: (CIT): In today's lecture, Dr. Shafer will illustrate how another genomic-scale technology, the Achilles' heel RNA interference genetic screen, has revealed the pathological role of B cell-specific transcription factors in multiple myeloma, a malignancy of plasma cells. These observations exemplify a new notion in cancer biology, termed non-oncogene addiction.
Subjects: Interferon Regulatory Factors--immunology
Multiple Myeloma--genetics
Multiple Myeloma--immunology
Transcription, Genetic--immunology
Publication Types: Lectures
Webcasts
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NLM Classification: WH 540
NLM ID: 101475739
CIT Live ID: 6736
Permanent link: http://videocast.nih.gov/launch.asp?14526