Disease relevance of IGH@

• Chromosomal translocations affecting the IGH locus and various oncogene loci are recurrent in many types of systemic B-cell lymphomas [1].
• This study identifies FOXP1 as a new translocation partner of IGH in a site-dependent subset of MALT lymphomas [2].
• The clonal relatedness was demonstrated in 9 of 11 pairs of matched diagnostic tumors and their relapses as determined by IGH gene rearrangement analysis and/or the CGH profiles [3].
• We show that endemic (eBL), sporadic (sBL), and acquired immunodeficiency syndrome-associated (AIDS-BL) forms of Burkitt lymphoma (BL) carrying t(8;14) chromosomal translocations display different breakpoints within the immunoglobulin heavy-chain locus (IGH) on chromosome 14 [4].
• From a bacteriophage lambda library prepared from a lymphoma characterized by a t(3;14)(q27;q32), genomic clones were isolated using a probe from the immunoglobulin heavy chain locus (IGH) joining region [5].

High impact information on IGH@

• 2D-DE, as illustrated here for the IGH gene cluster, has general application in the development of large scale physical maps of gene and repeat families [6].
• This analysis revealed that the human QIN gene maps to chromosome region 14q11.2-->14q32, between the TCR and IGH loci [7].
• The degree of linkage disequilibrium measured between IGH polymorphic loci was then compared with the physical distance separating the loci [8].
• Molecular cloning of the immunoglobulin heavy-chain locus (IGH) of this cell line revealed an unknown segment linked 5' to IGH [9].
• In most eBL (13 out of 16) the breakpoints were mapped within or 5' to the IGH joining (JH region on chromosome 14 and outside the MYC locus on chromosome 8 [4].

Chemical compound and disease context of IGH@

• IGH V3-23*01 and its allele V3-23*03 differ in their capacity to form the canonical human antibody combining site specific for the capsular polysaccharide of Haemophilus influenzae type b [10].

Biological context of IGH@

• Fluorescence in situ hybridization studies showed that the immunoglobulin heavy chain locus (IGH) was rearranged on chromosome 14 [2].
• Activation of an oncogene via its juxtaposition to the IGH locus by a chromosomal translocation or, less frequently, by genomic amplification is considered a major mechanism of B-cell lymphomagenesis [11].
• Using DNA fiber fluorescence in-situ hybridization (FISH) and 3-color interphase FISH, 2 cases of follicular lymphoma were identified in which the BCL2 gene was excised from 18q21 and inserted into the immunoglobulin heavy chain (IGH) locus at 14q32 [12].
• Reverse-transcriptase polymerase chain reaction showed expression of a unique hybrid IGH-BCL2 transcript involving the transcription initiation site I(mu) [13].
• CONCLUSION: The c-MYC/IGH fusion gene of DLCL is identical to that of the sporadic type of BL (sBL) [14].

Anatomical context of IGH@

• The t(14;18)(q32;q21) involving the MALT1/MLT and IGH genes has been identified recently as a recurrent abnormality in mucosa-associated lymphoid tissue (MALT) lymphomas [15].
• This is the first example of a t(14;18) translocation that results from an illegitimate IGH class-switch recombination during the germinal center B-cell stage [13].
• This study identifies IGH as a new translocation partner of MALT1 in MALT lymphomas, which tend to arise frequently at sites other than the gastrointestinal tract and lung [16].
• Among a total of 66 cases, t(14;18)(q32;q21) involving IGH and MALT1 was detected in MALT lymphomas of the liver (4 of 4), skin (3 of 11), ocular adnexa (3 of 8), and salivary gland (2 of 11), but did not occur in MALT lymphomas of the stomach (n = 10), intestine (n = 9), lung (n = 7), thyroid (n = 4), or breast (n = 2) [16].
• To define the exact incidence of illegitimate IGH rearrangements and the respective incidence of partner genes cloned to date, we analyzed 141 patients with either multiple myeloma (MM, n = 127) or primary plasma cell leukemia (PCL, n = 14) using fluorescence in situ hybridization [17].

Associations of IGH@ with chemical compounds

• The immunoglobulin heavy chain (IGH) gene cluster and the gene coding for the brain form of the enzyme creatine kinase (CKB) have previously been localized to chromosome 14, at 14q32.3 and 14q32, respectively [18].
• Using DNA extracted from formalin-fixed/paraffin-embedded tumors in all cases, we identified monoclonal IGH bands in 54 of 55 cases with the FR1c/J(H) primer; a monoclonal IGH band was amplified using another IGH primer set, FR256/J(H), in the remaining case [19].

Physical interactions of IGH@

• Sequence analysis showed that the genomic breakpoint is localized between the S(mu) region of the IGH complex and the first intron of BCL2 [13].

Enzymatic interactions of IGH@

• Hybridization studies with various DNA probes from the IGH locus as well as the BCL2 gene demonstrated that the mu-constant gene was deleted on the functional IGH allele of FL-318G cells, and that the cells produced abundant productive gamma-chain messages [20].

Regulatory relationships of IGH@

• This may be one possible mechanism of deregulating FOXP1 expression by placing it under the control of IGH enhancers [21].

Other interactions of IGH@

• Translocations involving the MYC locus were detected in six cases, five of them derived from a MYC/IGH juxtaposition and one from a translocation involving a non-IG gene partner [1].
• Rearrangements of the BCL6 locus were detected in five B-cell lymphomas of the leg, and involved IGH (two cases), IGL (one case), and non-IG genes (two cases) [1].
• V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma [12].
• Taken together these results support the hypothesis that enhanced BCL10 expression caused by translocation to the IGH locus can promote formation of MALT lymphomas [22].
• The translocation brought the Sgamma2 region of a productive IGH allele 20 approximately 30 kbp upstream of FCGR2B [23].

Analytical, diagnostic and therapeutic context of IGH@

• Sequence analysis of the V(H) region of the functional nontranslocated IGH allele showed multiple shared somatic mutations but also a high intraclonal variation (53 differences in 15 clones), compatible with the lymphoma cells staying in or re-entering the germinal center [13].
• With the use of DNA-fiber fluorescent in situ hybridization, a BCL2 protein positive follicular lymphoma with a novel BCL2 breakpoint involving the immunoglobulin heavy chain (IGH) switch mu (S(mu)) region instead of the J(H) or D(H) gene segments was identified [13].
• Genomic DNA extracted from tumor tissues was subjected to long-distance polymerase chain reaction (LD-PCR) using oligonucleotide primers for exon 2 of c-MYC and for the four constant region genes of IGH [14].
• We studied the exact configuration of both the nontranslocated IGH allele and the MYC/IGH breakpoint by applying a combination of low- and high-resolution methods (interphase FISH, DNA fiber FISH, long-distance PCR, and Southern blotting) on 16 BL [24].
• Molecular cloning of a 5'-BCL2/IGH junction demonstrated recombination of the two affected genes in divergent orientation [25].

References