Disease relevance of BCL11B

• A novel t(6;14)(q25-q27;q32) in acute myelocytic leukemia involves the BCL11B gene [1].
• To our knowledge, this is the first report implicating BCL11B in hematological malignancies [1].
• BCL11B is a homolog to BCL11A (2p13), a highly conserved gene implicated in mouse and human leukemias [1].
• The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2) [2].
• A cryptic chromosome rearrangement, t(5;14)(q35.1;q32.2), recently identified in pediatric acute lymphoblastic leukemia (ALL), targets activation of TLX3 at 5q35.1 by juxtaposition with a region downstream of BCL11B at 14q32 [2].

High impact information on BCL11B

• BCL11A and BCL11B are transcriptional regulators important for lymphopoiesis and previously associated with hematopoietic malignancies [3].
• HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32) [4].
• Here we show both in transformed and primary CD4(+) T cells that BCL11B participates in the control of the interleukin-2 (IL2) gene expression following activation through T-cell receptor (TCR) [3].
• It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5 [4].
• BCL11B participates in the activation of IL2 gene expression in CD4+ T lymphocytes [3].

Biological context of BCL11B

• BCL11A was also highly homologous to another gene (BCL11B) on chromosome 14q32 [5].
• FISH experiments using genomic probes showed that the breakpoint on 14q32.2 was within bacterial artificial chromosome RP11-782I5 and revealed BCL11B as the only candidate gene in the region [1].
• Our data pinpoint a regulatory region far downstream of BCL11B effecting ectopic homeobox gene activation [2].
• Specifically, disruption of the BCL11B (B-cell chronic lymphocytic leukemia/lymphoma 11B) locus is linked to T-cell acute lymphoblastic leukemia, and the loss of heterozygosity in mice results in T-cell lymphoma [6].
• Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting proteins 1 and 2 [CTIP1/Evi9/B cell leukaemia (Bcl) l1a and CTIP2/Bcl11b respectively] are highly related C(2)H(2) zinc finger proteins that are abundantly expressed in brain and the immune system, and are associated with immune system malignancies [7].

Anatomical context of BCL11B

• BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter [6].
• CTIP2 is essential for both T cell development and axonal projections of corticospinal motor neurons in the central nervous system [8].

Associations of BCL11B with chemical compounds

• BCL11B complexes from T lymphocytes possess trichostatin A-sensitive histone deacetylase activity, confirming the functionality of the complexes [6].
• CTIP2 Associates with the NuRD Complex on the Promoter of p57KIP2, a Newly Identified CTIP2 Target Gene [8].

Regulatory relationships of BCL11B

• We report that CTIP2 represses Sp1- and COUP-TF-mediated activation of HIV-1 gene transcription and viral replication as a result of physical interactions with COUP-TF and Sp1 in microglial nuclei [9].

Other interactions of BCL11B

• Here, we demonstrate the association of the endogenous BCL11B with the nucleosome remodeling and histone deacetylase (NuRD) complex, one of the major transcriptional corepressor complexes in mammalian cells [6].
• Screening of 37 other T-ALLs revealed one additional case with expression of the BCL11B-TRDC fusion transcript [10].
• The TRDV1-BCL11B joining region was 1344 bp long and contained fragments derived from 20q11.22, 3p21.33 and from 11p12, indicating the complex character of this aberration [10].
• Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2 (CTIP2), also known as Bcl11b, is a transcriptional repressor that functions by direct, sequence-specific DNA binding activity or by recruitment to the promoter template by interaction with COUP-TF family members [8].
• We report a novel chromosomal translocation in a T-ALL patient that maps upstream of the HOXA13 gene and downstream of the BCL11B/CTIP2 locus [11].

Analytical, diagnostic and therapeutic context of BCL11B

• Using laser confocal microscopy CTIP2 was found to colocalize with Sp1, COUP-TF and the heterochromatin-associated protein Hp1alpha, which is mainly detected in transcriptionally repressed heterochromatic region [9].

References