Deregulation of BANK1, a Novel IGH Translocation Partner, Indicates a Potential Pathogenic Role in B Cell Lymphomas
Jiong Yan, Kui Nie, Susan Mathew, Daniel M Knowles, Attilio Orazi, Wayne Tam. Weill Cornell Medical College, New York, NY
Background: Identification of partner genes residing at immunoglobulin heavy chain (IgH)-associated translocation breakpoints by molecular cloning has been instrumental in understanding B-cell lymphomagenesis. We recently demonstrated by conventional karyotyping a novel reciprocal translocation, t(4;14)(q23;q32), in a case of gastric polymorphic/monomorphic post-transplant lymphoproliferative disorder (PTLD) and subsequently identified BANK1 as a novel IGH translocation partner. BANK1 (B-cell scaffold protein with ankyrin repeats 1) is a B-cell-specific adaptor protein that regulates B cell receptor signal transduction. Its precise role remains unclear but a knock-out mouse model suggested a negative role for BANK1 on B cell activation.
Design: The t(4;14)(q23;q32) breakpoint was cloned by inverse PCR. BANK1 mRNA expression levels were determined by qRT-PCR in the index case, 24 B lymphoma cell lines, 24 primary diffuse large B cell lymphomas (DLBCL), as well as 3 sets each of naïve, germinal center and memory B cells (NB, GCB, MB). A ≥ 50% decrease compared to the median BANK1 expression in GCB was used as a cutoff for expression reduction.
Results: The novel translation involves the Sα region of IgH and BANK1 located at chromosome 4q23. It juxtaposes the IgH gene (without the Em enhancer) to intron 1 of BANK1 in an opposite orientation, resulting in removal of the major BANK1 promoter and reduction of BANK1 levels by 74% compared to GCB. Interphase FISH using break-apart BANK1 probes confirmed breakpoint in the index case but did not identify translocations in an additional 15 PTLDs. BANK1 levels in normal B cells are differentiation stage-dependent, being 5-fold lower in GCB compared to NB and MB. Among cell lines, reduced BANK1 expressions were observed in 5/8 Burkitt lymphoma, 7/9 DLBCL, 4/4 primary effusion lymphoma and 3/3 Hodgkin lymphoma. 15 of 24 primary DLBCL also showed reduced BANK1 expressions, and reduction in 11 cases was 75% or more. There is no significant difference in BANK1 expression between immunohistochemically defined GCB and non-GCB DLBCL subtypes.
Conclusions: We describe an unusual case in which a novel IGH translocation, instead of activating expression of its partner gene, down-regulates BANK1 by dislocating its promoter. BANK1 expression is also reduced in the majority of B lymphoma cell lines and primary DLBCL examined. Our study indicates a potential tumor suppressor role for BANK1 in mature B cell malignancies and illustrates an undescribed mechanism of gene deregulation by IGH translocations.
Monday, March 19, 2012 9:15 AM
Platform Session: Section C, Monday Morning