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Blood Adv. 2017 July 11; 1(16): 1259–1260.
Published online 2017 July 3. doi:  10.1182/bloodadvances.2017007401
PMCID: PMC5728550

Structure and diversification of immunoglobulin genes in African Burkitt lymphoma


The article by Lombardo and colleagues1 described high throughput sequencing of the immunoglobulin (Ig) heavy and light chain genes from African Burkitt lymphomas (BLs). On the basis of their analysis and, in particular, because of the frequent lack of detection of Ig DHJH or VHDHJH rearrangements on the nonexpressed Ig heavy (IgH) chain allele, as well as ongoing mutation on the nonexpressed allele, the authors conclude that BLs derive from an abnormal B-cell progenitor.

I would like to point out several features of the diversification processes of human Ig genes and the pathogenesis of BLs that were not considered in the interpretation of the data and that bring into question the conclusions in the article by Lombardo et al.1

First, the article states that all normal B cells undergo biallelic DHJH rearrangement at the pro-B cell stage. This statement is correct for murine B cells but does not hold true for human B-cell progenitors. Although there are few studies on this issue, a detailed Southern blot analysis revealed that about 20% of human B cells lack DHJH or VHDHJH rearrangements on the nonexpressed IgH allele,2 so that a considerable fraction of normal human B cells shows a germline configuration of the nonexpressed IgH locus.

Second, it is physiological for human B cells and not an abnormal feature of BL cells that nonproductive VHDHJH rearrangements undergo somatic hypermutation as efficient as the productive alleles.3,4 The nonproductive VHDHJH rearrangements are apparently well transcribed (which is considered an essential prerequisite for being targeted by somatic hypermutation), but because of premature stop codons, the messenger RNA (mRNA) is fast degraded by the process of nonsense-mediated decay and other mechanisms, so that in the steady state, one finds few transcripts from the nonproductive allele.5,6

Third, practically all BLs carry translocations of the MYC oncogene into 1 of the Ig loci, mostly the IgH locus.7 These translocations either target 1 of the IgH switch regions or they occur as mistakes of somatic hypermutation and are then found within or close to rearranged Ig V region genes.4,7 In endemic BL, the MYC translocations seem to be frequent in or near rearranged IgH V region genes.8 If the translocation disrupts the nonexpressed VHDHJH rearrangements (the translocations do not disrupt the productive allele, because BLs are nearly always surface Ig-positive), then the original rearrangement cannot be further amplified by polymerase chain reaction (PCR).

Fourth, it is to be expected that some VHDHJH rearrangements were not successfully amplified because of a technical failure of the PCR. The rearrangements were amplified with primers binding to the VH leader region and to the IGHJ gene segments. In both regions, somatic hypermutation occurs, and a single mutation in the Ig V region gene close to the 3′ of the primer binding site will impair efficient amplification of such rearrangements. Thus, when studying mutated B cells, a fraction of mutated Ig V gene rearrangements will likely not be amplified with a strategy using primers in the somatic mutation target sequence. Moreover, about 40% of mutated nonproductive VHDHJH rearrangements of normal human B cells carry deletions and/or insertions/duplications, which are sometimes several hundred bases long and thus can also prevent successful amplification by PCR.4 The chance to amplify mutated Ig V genes is higher when using mRNA and C-region–specific primers instead of J gene segment primers because there are no mutations in the C-region exons. But for nonproductive alleles, as pointed out above, one will likely miss them because of the low steady state mRNA levels of such rearrangements.

Taken together, the frequent failure to detect 2 VHDHJH rearrangements or 1 VHDHJH and 1 DH-JH rearrangement in the endemic BLs can be explained by (1) the physiological germ line configuration of the IgH locus in a fraction of B cells, (2) the destruction of VHDHJH rearrangements through MYC translocation events in germinal-center B cells as a by-product of somatic hypermutation, and (3) occasional failure to amplify VHDHJH rearrangements because of mutations at primer binding sites or larger deletions/duplications. Although exact frequencies for these 3 factors are difficult to estimate, together they can well explain the experimental result in the study on endemic BL. In addition, the detection of somatic mutations in nonproductive VHDHJH rearrangements is a physiological event and not a marker for an abnormal B cell. Overall, although it cannot be excluded that the B-cell precursors of BL have some peculiarities (eg, they are selected to express particular IGHV segments), the features described in the study by Lombardo et al1 cannot be taken as convincing arguments for a derivation of BL from an abnormal B-cell progenitor and for aberrant mutational processes in these cells.

Finally, a remarkable observation in the study by Lombardo et al1 is the frequent detection of somatic mutations in DHJH joints. There is very little information on how frequently this occurs in normal or malignant human B cells. For the mouse, it has been reported that the mutation frequency of DHJH joints is only about 10% of that seen in VHDHJH rearrangements.9


Contribution: R.K. wrote the letter.

Conflict-of-interest disclosure: The author declares no competing financial interests.

Correspondence: Ralf Küppers, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, Virchowstr 173, 45122 Essen, Germany; e-mail: ed.nesse-ku@sreppeuk.flar.


1. Lombardo KA, Coffey DG, Morales AJ, et al. High-throughput sequencing of the B-cell receptor in African Burkitt lymphoma reveals clues to pathogenesis. Blood Adv. 2017;1(9):535-544.
2. Walter MA, Dosch HM, Cox DW A deletion map of the human immunoglobulin heavy chain variable region. J Exp Med. 1991;174(2):335-349. [PMC free article] [PubMed]
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5. Chemin G, Tinguely A, Sirac C, et al. Multiple RNA surveillance mechanisms cooperate to reduce the amount of nonfunctional Ig kappa transcripts. J Immunol. 2010;184(9):5009-5017. [PubMed]
6. Tinguely A, Chemin G, Péron S, et al. Cross talk between immunoglobulin heavy-chain transcription and RNA surveillance during B cell development. Mol Cell Biol. 2012;32(1):107-117. [PMC free article] [PubMed]
7. Küppers R, Dalla-Favera R Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene. 2001;20(40):5580-5594. [PubMed]
8. Neri A, Barriga F, Knowles DM, Magrath IT, Dalla-Favera R Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphoma. Proc Natl Acad Sci USA. 1988;85(8):2748-2752. [PubMed]
9. Roes J, Hüppi K, Rajewsky K, Sablitzky F V gene rearrangement is required to fully activate the hypermutation mechanism in B cells. J Immunol. 1989;142(3):1022-1026. [PubMed]

Articles from Blood Advances are provided here courtesy of American Society of Hematology