Cloning and mapping of cat (Felis catus) immunoglobulin and T-cell receptor genes
IMMUNOGENETICS
Authors: Cho, KW; Youn, HY; Okuda, M; Satoh, H; Cevario, S; O'Brien, SJ; Watari, T; Tsujimoto, H; Hasegawa, A
Abstract
Molecular cloning and chromosomal mapping of the cat immunoglobulin (Ig) and T-cell receptor (TcR) genes were carried out to provide basic information for genetic analysis of immunologic diseases including leukemias and lymphomas in cats. We cloned two ii: constant genes, IGHM and IGHG and three Ten constant genes, TRAC, TRGC, and TRDC, by polymerase chain reaction (FCR) amplification of cDNA from cat peripheral blood mononuclear cells. For chromosomal mapping of the ip and TcR loci including the IGK, TC;I, and TRB on the cat genome, we performed PCR screening of DNAs li-om 37 cat x rodent somatic cell hybrids by using specific primers for the given genes. Consequently, three loci for IGH, TRA, and TRD, and two loci for TRB and TRG were found to be syntenic and assigned to cat chromosomes (FCA) B3 and A2, respectively. Further, IGK and IGL loci were mapped on FCA A3 and D3, respectively. These findings support the notion that the genetic linkages between the Ig and TcR genes are extensively conserved between humans and cats.
Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma
SCIENCE TRANSLATIONAL MEDICINE
Authors: Jain, Neeraj; Hartert, Keenan; Tadros, Saber; Fiskus, Warren; Havranek, Ondrej; Ma, Man Chun John; Bouska, Alyssa; Heavican, Tayla; Kumar, Dhiraj; Deng, Qing; Moore, Dalia; Pak, Christine; Liu, Chih Long; Gentles, Andrew J.; Hartmann, Elena; Kridel, Robert; Smedby, Karin Ekstrom; Juliusson, Gunnar; Rosenquist, Richard; Gascoyne, Randy D.; Rosenwald, Andreas; Giancotti, Filippo; Neelapu, Sattva S.; Westin, Jason; Vose, Julie M.; Lunning, Matthew A.; Greiner, Timothy; Rodig, Scott; Iqbal, Javeed; Alizadeh, Ash A.; Davis, R. Eric; Bhalla, Kapil; Green, Michael R.
Abstract
The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin mu (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.