Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF.
Recently, high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements have been categorized separately from diffuse large B-cell lymphoma or BL.
MYC translocation is a defining feature of Burkitt lymphoma (BL), and the new category of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 translocations, and occurs in 6% to 15% of diffuse large B-cell lymphomas (DLBCLs).
B-cell lymphomas with translocations involving MYC and BCL6 have morphologic and immunophenotypic features suggestive of Burkitt lymphoma or gray zone lymphoma, and they tend to be diagnosed mainly in women, often in extranodal locations.
MYC gene alterations in diffuse large B-cell lymphomas and in B-cell lymphomas, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma are frequently associated with BCL2 or/and BCL6 translocations conferring a very aggressive behavior.
Although there are conflicting data regarding prognostic implications of isolated MYC aberrancy in these non-BLs, the co-occurrence of MYC rearrangements and either the antiapoptotic gene B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) or the transcriptional repressor BCL6 leads to an entity termed double-hit B-cell lymphoma (DHL) (or triple-hit if all 3 abnormalities are observed) with a particularly poor prognosis and no established treatment paradigms.
In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status).
Double-hit (DH) lymphomas with MYC and either BCL2 (DH-BCL2/MYC) or BCL6 (DH-BCL6/MYC) rearrangements are considered very aggressive, many of which are now included in the category B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (DLBCL/BL).
We identified ID3 mutations in lymphomas with chromosomal aberrations at cMYC and either BCL2 or BCL6 at a frequency intermediate between that of DLBCL and Burkitt lymphoma, hinting at a common pathway in lymphomagenesis for a subset of patients with DHL.
We used Burkitt's lymphoma (BL) lines, as a model system of normal human GC B cells, to examine the effect of type I IFNs on the expression of BCL-6, the major regulator of the GC reaction.
The expression of CD10 and BCL6 but not BCL2, a high Ki-67 PI (>90%) and a C-MYC rearrangement but not BCL2 or BCL6 rearrangement are the features of BL.
In addition, transfection of a VP16-BCL6 zinc fingers fusion protein, which competes with the binding of endogenous BCL6 in a Burkitt lymphoma cell line, increases PDCD2 protein expression and apoptosis, and knockdown of the PDCD2 protein in this cell line by PDCD2-specific small interfering RNA duplexes inhibits apoptosis.
We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities.
Translocations involving 3q27 that affect the BCL6 gene are common and specific chromosomal abnormalities in B-cell precursor non-Hodgkin lymphoma (mainly diffuse large-cell and follicular lymphoma), but they have not been reported in Burkitt lymphoma.
PTLD expressing the BCL6(+)/MUM1(+/-)/CD138(-) profile reflect B-cells actively experiencing the GC reaction and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma.
We analyzed 74 adult gray zone and 10 reference pediatric BL using immunohistochemistry (Ki-67, CD10, bcl2, bcl6) and fluorescence in situ hybridization (FISH) for MYC, BCL2, and BCL6 breakpoints.
Retrospective work-up of the 29-year-old tumor blocks revealed the typical histologic appearance and phenotype (CD20, CD10, BCL-6 positive) of Burkitt's lymphoma (BL) with a proliferation rate of 95%.
These data expand the spectrum of B-cell non-Hodgkin's lymphomas associated with BCL-6 5' mutations and have implications for the pathogenesis, histogenesis and clinical monitoring of Burkitt's lymphoma.