The t(14;18)(q32;q21)/IGH-MALT1 translocation in MALT lymphomas is a CpG-type translocation, but the t(11;18)(q21;q21)/API2-MALT1 translocation in MALT lymphomas is not

To the editor:

In a recent issue of Blood, Murga Penas et al identified a novel cluster region on MALT1 from t(14;18)(q32;q21) IGH-MALT1 translocations in MALT lymphomas, which bears many similarities to the bcl-1 major translocation cluster (MTC) from mantle cell lymphomas and the bcl-2 major breakpoint region (MBR) from follicular and diffuse large B-cell lymphomas.¹ 

We have previously reported that pro-B/pre-B stage translocation breakpoints are highly clustered to the dinucleotide sequence CpG, including those at the bcl-1 MTC, bcl-2 MBR, bcl-2 intermediate cluster region (icr), bcl-2 minor cluster region (mcr), and E2A cluster region from E2A-PBX1 translocations in pre-B ALLs.²  After plotting the reported breakpoints, we find that CpG proximity is also a feature of the MALT1 cluster region (see figure). Four of the 8 breakpoints are directly at CpGs (P < .002) and breakpoints are much closer to CpGs than expected by random chance (P < .005). All but 1 are within 8 bp of CpG (dark gray bars in the histogram), far more than if breakpoints were randomly distributed throughout the region (light gray bars in the histogram). Methods have been described previously.² 

While the IGH-MALT1 translocation is found in approximately 10% of MALT lymphomas, the t(11;18)(q21;q21) API2-MALT1 translocation is more common, found in approximately 30% of MALT lymphomas, but also involves the MALT1 locus. The IGH-MALT1 translocation involves a very focused (86 bp) region upstream of the MALT1 promoter, joins to the immunoglobulin heavy chain RSS, involves a CpG-type mechanism, and contains N- and T-nucleotides in its junctions. By contrast, the API2-MALT1 translocation involves a very wide (29 kb) region covering several exons and introns of the MALT1 gene, joins to a 4.5-kb region of the API2 intron, and its junctions mainly use microhomology, without N- or T-nucleotides.^3-5  In our analysis of API2-MALT1 translocations, none of the 40 breakpoints on API2 and none of the 41 breakpoints on MALT1 occur at CpGs (p = 1), and breakpoints are no closer to CpGs than expected by random chance (P > .2).

We concur with the observation of Murga Penas et al that none of the MALT1 breakpoints is compatible with a standard V(D)J recombination-type mechanism. The presence of N-nucleotides likely added by TdT, T-nucleotides, and the involvement of the V(D)J recombination signal sequences (RSS) at the immunoglobulin heavy chain locus side of the translocation are all features that are virtually pathognomonic for the pro-B/pre-B stage of development, though the lymphoma itself may originate from a later stage of development than the translocation. By contrast, the API2-MALT1 translocation, which also involves the MALT1 locus, has none of these features and likely occurs either before the pro-B/pre-B stage (ie, at the lymphoid-myeloid hematopoietic stem cell stage) or after the pro-B/pre-B stage (ie, at the mature B-cell stage). It is especially interesting that a single clinical entity—MALT lymphomas—would feature translocations from 2 different stages of B-cell development, but involve the same MALT1 locus. Our analysis affirms the authors' deduction that the bcl-1, bcl-2, and IGH-MALT1 translocations all share a common mechanism, but additionally shows that, like the bcl-1 and bcl-2 translocations, the IGH-MALT1 is a member of the CpG-type translocation family, which appears unique to the B-cell lineage and the pro-B/pre-B stage of development.