Disease relevance of BCL11A

• 1. BCL11A coamplified with REL in B-NHL cases and HD lymphoma cell lines with gains and amplifications of 2p13, suggesting that BCL11A may be involved in lymphoid malignancies through either chromosomal translocation or amplification [1].
• The t(2;14)(p13;q32.3) involving the BCL11A and IGH genes is a rare but recurrent chromosomal aberration in B-cell malignancies [2].
• Hitherto, juxtaposition of BCL11A and IGH has only been described in B-cell chronic lymphocytic leukemia (B-CLL) and immunocytoma [2].
• EBV was integrated via the terminal repeats (TR), and integration sites located in the clone RP11-440P5 on chromosome 2, between two oncogenes, REL and BCL11A, which is apart from approximately 350 kbp from each other [3].
• BCL11B is a homolog to BCL11A (2p13), a highly conserved gene implicated in mouse and human leukemias [4].

High impact information on BCL11A

• In 4 CLL cases with unmutated VH genes, a common minimal 3.5-Mb gain of 2p16 spanning the REL and BCL11A oncogenes was identified, implicating these genes in the pathogenesis of CLL [5].
• BCL11A and BCL11B are transcriptional regulators important for lymphopoiesis and previously associated with hematopoietic malignancies [6].
• This CpG island was associated with a Krüppel zinc finger gene (BCL11A), which is normally expressed at high levels only in fetal brain and in germinal center B-cells [1].
• BCL11A was also highly homologous to another gene (BCL11B) on chromosome 14q32 [1].
• However, transcriptional repression mediated by ARP1 acting through CTIP1 did not appear to involve recruitment of a trichostatin A-sensitive histone deacetylase(s) to the template, suggesting that this repression pathway may be distinct from that utilized by several other nuclear receptors [7].

Biological context of BCL11A

• There were 3 major RNA isoforms of BCL11A, differing in the number of carboxy-terminal zinc fingers [1].
• Nonetheless, chromatin immunoprecipitation assays revealed that expression of BCL11A in mammalian cells resulted in deacetylation of histones H3 and/or H4 that were associated with the promoter region of a reporter gene [8].
• The minimal region of gain contained 2 candidate oncogenes, REL and BCL11A [9].
• This study examined the involvement of REL and BCL11A loci in 44 primary cases of cHL by combined immunophenotyping and interphase cytogenetics (FICTION) [9].
• A selection procedure was employed to isolate high-affinity DNA binding sites for CTIP1 [10].

Anatomical context of BCL11A

• 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 [10].
• Furthermore, EVI9 was down-regulated during myeloid differentiation of HL60 cells induced by all-trans-retinoic acid, whereas the expression remained during monocytic differentiation induced by phorbol 12-myristate 13-acetate [11].
• BCL11A-XL partitions into the nuclear matrix and colocalizes with BCL6 in nuclear paraspeckles [12].
• Western blot data for BCL11A-XL expression coupled with data previously published for BCL6 indicates that these genes are expressed abundantly in germinal-center-derived B cells but that expression is extinguished upon terminal differentiation to the plasma cell stage [12].

Associations of BCL11A with chemical compounds

• In both cases, BCL11A-mediated transcriptional repression is only minimally reversed by trichostatin A, suggesting the possible lack of involvement of class I or II histone deacetylases [8].

Physical interactions of BCL11A

• SIRT1 was found to interact directly with BCL11A and was recruited to the promoter template in a BCL11A-dependent manner leading to transcriptional repression [8].
• These results demonstrate that CTIP1 is a sequence-specific DNA binding protein and a bona fide transcriptional repressor that is capable of functioning independently of COUP-TF family members [10].

Other interactions of BCL11A

• These findings define a role for SIRT1 in transcriptional repression mediated by BCL11A in mammalian cells [8].
• COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein [10].
• Genes recently shown to be involved in such translocations include BCL11A and MALT1 [13].

Analytical, diagnostic and therapeutic context of BCL11A

• One cHL displayed selective amplification of the REL locus not affecting BCL11A; another case studied by FICTION and a cHL with cytogenetic 2p change investigated by fluorescence in situ hybridization showed signal patterns suggesting breakpoints in the region spanned by the REL probe [9].
• Real-time quantitative PCR detected REL and BCL11A gene amplifications in the nine patients with gains at 2p13-p16 and only in one additional patient with normal chromosome 2 [14].

References