MYC translocation‐negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation

Abstract

The molecular feature of Burkitt lymphoma (BL) is the translocation that places c-Myc under the control of immunoglobulin gene regulatory elements. However, there is accumulating evidence that some cases may lack an identifiable MYC translocation. In addition, during the EUROFISH project, aiming at the standardization of FISH procedures in lymphoma diagnosis, we found that five cases out of 35 classic endemic BLs were negative for MYC translocations by using a split-signal as well as a dual-fusion probe. Here we investigated the expression pattern of miRNAs predicted to target c-Myc, in BL cases, to clarify whether alternative pathogenetic mechanisms may be responsible for lymphomagenesis in cases lacking the MYC translocation. miRNAs are a class of small RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have reported their involvement in cancer and their association with fragile sites in the genome. They have also been shown to control cell growth, differentiation, and apoptosis, suggesting that these molecules could act as tumour suppressors or oncogenes. Our results demonstrated a modulation of specific miRNAs. In particular, down-regulation of hsa-let-7c was observed in BL cases, compared to normal controls. More interestingly, hsa-mir-34b was found to be down-regulated only in BL cases that were negative for MYC translocation, suggesting that this event might be responsible for c-Myc deregulation in such cases. This hypothesis was further confirmed by our in vitro experiments, which demonstrated that increasing doses of synthetic hsa-mir-34b were able to modulate c-Myc expression. These results indicate for the first time that hsa-mir-34b may influence c-Myc expression in Burkitt lymphoma as the more common aberrant control exercised by the immunoglobulin enhancer locus.

Simple karyotype and bcl-6 expression predict a diagnosis of Burkitt lymphoma and better survival in IG-MYC rearranged high-grade B-cell lymphomas

“…14 In addition, rare cases that are otherwise characteristic of Burkitt lymphoma but lack MYC-IG rearrangement are acceptable for Burkitt lymphoma as these cases bear a Burkitt-like molecular signature, 13,14 and may upregulate MYC expression by alternative mechanisms possibly involving the modulation of microRNA. 22 Although the new diagnostic criteria are clearly outlined, the practical application is not always straightforward. For example, cases with features slightly deviating from the typical medium-sized monomorphous cytomorphology may be acceptable for Burkitt lymphoma, 14 whereas cases with greater cytomorphological variations would be classified as unclassifiable or diffuse large B-cell lymphoma.…”

Post‐transplant Burkitt lymphoma is a more aggressive and distinct form of post‐transplant lymphoproliferative disorder

“…Others have shown that classic Burkitt morphological features with a very high proliferation fraction should still be considered as a BL, even when there is a negative MYC translocation. 24 This group has found an alternative mechanism of c-MYC upregulation in these rare negative cases not identified by the commercial FISH probes. 24 Moreover, studies have shown that those cases morphologically diagnosed BL, with a very high proliferation index and negative c-MYC, who were treated with less aggressive chemotherapy for a DLBCL, tended to have worse outcomes.…”

The miR-34 family in cancer and apoptosis

“…An example is c-MYC, which seems to be regulated mainly by miR-34b/c. 53,54,46 This can presumably be explained by the enhanced complementarity between the miR-34b seed sequence and the seed-matching sequence in the c-MYC 3 0 -UTR, when compared with miR-34a (Table 1; Figure 2b). The induction of miR-34 genes allows p53 to regulate the expression of a large number of proteins, even after their transcripts have already been synthesized.…”