Burkitt Lymphoma: From Pathogenesis to Current Treatments

Dear Colleagues,

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that affects children and adults. Historically, endemic BL (eBL), non-endemic (sporadic) BL (sBL), and immunodeficiency-associated BL have been recognized. However, an almost mutual exclusivity could be demonstrated between the presence of EBV and the detection of characteristic mutations in TCF3 and ID3 genes in eBL. The fact that EBV-positive BL cases harbor fewer driver mutations was also subsequently confirmed in sBL, leading to the awareness that subtyping into EBV⁺ and EBV⁻ BL might better capture the biological heterogeneity of BL; hence, a dual mechanism of transformation in BL was established: mutations-driven versus virus-driven. Thus, EBV positivity (not epidemiology) is now considered the defining feature of clinical subtypes of BL in WHO-HAEM5.

BL is diagnosed on the basis of morphology, immunophenotyping, and the deregulation of MYC.  However, no single parameter can be used on its own as the gold standard for diagnosing BL; a combination of several diagnostic techniques is necessary. The diagnosis of some cases can be challenging and other types of aggressive B-cell lymphomas, including high-grade B-cell lymphomas with 11q alterations, should be carefully excluded.

BL can be effectively treated in children and adolescents with short-duration, high-dose-intensity multiagent chemotherapy regimens; however, the prognosis of BL is still poor in low-resource settings. The shortcomings of current BL therapy approaches make the elucidation of new therapeutic avenues a substantial and reasonable aim. In this respect, proper characterization of the tumor microenvironment (TME) might help to identify alternative therapeutic targets in BL. In general, although reactive infiltrating lymphocytes are scarce, the macrophages forming the “starry sky” pattern, along with mesenchymal stem cells, stromal cells, and soluble factors, represent the main components of the TME of BL. The role of these macrophages in BL is not yet fully understood, but they might contribute to tumor progression owing to their secretion of chemokines and cytokines. Moreover, the dynamic process of macrophage plasticity may be responsible for a more aggressive clinical course. Novel therapeutic strategies able to induce TAM repolarization have been introduced and may have the potential to be a game-changer in the fight against BL and improve patient outcomes, opening alternative therapeutic avenues for therapy in refractory patients.

The aim of this Special Issue will be to investigate the pathogenesis of BL in depth, in relation to possible new therapeutic approaches. There are still many questions that need to be addressed regarding the differences between EBV-positive and EBV-negative BL, which may originate from cells at different steps of B-cell differentiation, different mechanisms of activation of BCR signaling, and MYC translocation. These goals can be achieved via the application of innovative molecular analyses such as whole-exome sequencing, RNA sequencing, methylation analysis, targeted NGS analysis, and proteomics, to name a few. The application of some of these techniques to routine practice could also improve the diagnosis of BL. 

One other issue would be to better define the distribution of EBV-positive cases in relation to age, geographical distribution, and possible associations with other infectious agents, following new evidence that the epidemiology of BL is changing in endemic areas.

Finally, are new therapeutic options for BL patients?

In this Special Issue, original research articles and reviews are welcome.

We look forward to receiving insightful contributions.

Prof. Dr. Lorenzo Leoncini
Prof. Dr. German K. Ott
Guest Editors

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• Burkitt lymphoma
• high-grade B-cell lymphoma
• EBV
• NGS
• whole-exome sequencing
• RNAseq
• methylation analysis
• tumor microenvironment
• immunotherapy
• chemotherapy