MYC in DLBCL: partners matter

Abstract

The biological effect of MYC translocation in DLBCL may be modulated by additional parameters that include the IG or non-IG partner gene involved in the translocation, the association with an additional translocation of the BCL2 or BCL6 genes in the so-called DH, the tumor cell context in which the alteration occurs such DLBCL, GCB or ABC, BCLu, and other factors such as the MYC or BCL2 protein levels. Additional studies are needed to explore other aspects such as the influence of somatic mutations in the tumor. Professional illustration by Patrick Lane, ScEYEnce Studios.BLOOD, 26 NOVEMBER 2015 x VOLUME 126, NUMBER 22 2439For personal use only. on May 12, 2018. by guest www.bloodjournal.org From subtypes of DLBCL, germinal center B-cell-like (GCB) or activated B-cell type (ABC), are not always considered. In addition, preliminary studies suggest that some biological aspects such as the partner gene in the MYC translocation or the levels of MYC or BCL2 protein expression may also influence tumor behavior. 2,4,6 The interplay of so many variables and the relative low frequency of aggressive lymphomas with MYC alterations make the development of appropriate studies challenging. However, this is exactly what Copie-Bergman and colleagues do in their study.1 The authors concentrated (in the evaluation of the MYC translocation partner, IG vs non-IG gene) on the outcome of 574 patients with DLBCL treated with immunochemotherapy in the context of clinical trials. They started using a MYC break-apart fluorescence in situ hybridization probe to detect any MYC translocation followed by IGH, IGK, and IGL fusion probes to confirm whether the partner was an IG or non-IG gene. MYC analysis was combined with the investigation of BCL2 and BCL6 translocations. MYC-Rs were found in 9% of the cases with a similar distribution of IG (48%) or non-IG (52%) as partner genes. Interestingly, only the rearrangement with IG had a negative effect on the outcome of the patients, and this impact was seen in cases with isolated MYC translocation and also in DH tumors. Concordant with previous messenger RNA studies, 7 the authors found significantly higher MYC protein expression in MYC-IG than in MYC-non-IG translocated cases, suggesting that MYC levels and its transcriptional regulator partner may be relevant in the behavior of the tumor. The study further clarifies other controversial issues. The prognostic impact of MYC-SH and MYC-DH was only observed in DLBCL with a GCB phenotype, suggesting that MYC activation may be more relevant in this subset of DLBCL. Intriguingly, MYC-SH translocations but not MYC-DH had an independent prognostic value from the International Prognostic Index or cell-of-origin classification. However, when MYC/BCL6-DH cases were excluded, then MYC/BCL2-DH also had an independent poor prognostic impact. The study included only 7 cases with MYC/ BCL6-DH but, interestingly, 6 of them were non-GCB and had a tendency to better prognosis than cases with MYC/BCL2-DH, which occurs almost exclusively in GCB tumors. Previous repo...

The 2016 revision of the World Health Organization classification of lymphoid neoplasms

“…They also better characterized the double-/triple-hit lymphomas, including identifying features that might mitigate the adverse clinical impact of MYC translocations. 68,[86][87][88] The criteria for BCLU, however, are vague and the diagnosis has not been used uniformly, limiting its utility as a diagnostic category. 68,86,87 All LBCL with MYC and BCL2 and/or BCL6 rearrangements will be included in a single category to be designated HGBL, with MYC and BCL2 and/or BCL6 rearrangements, except for cases that fulfill the criteria for a follicular or lymphoblastic lymphoma (Figures 4 and 5).…”

Diagnosis and classification of hematologic malignancies on the basis of genetics

“…MYC rearrangements are detected in 5% to 15% of DLBCL not otherwise specified (NOS) and are often associated with GCB phenotype (;70%). IG are the partner genes in nearly 50% of these cases (reviewed recently by Campo 101 ). Half of MYC-rearranged DLBCL also have concurrent BCL2 or, to a lesser extent, BCL6 translocations (so-called "double hit" [DH] or "triple hit" lymphoma) which have been reclassified as high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements in the 2016 WHO revision.…”

Altered TERT promoter and other genomic regulatory elements: occurrence and impact

“…81 Some of the somatic genetic rearrangements result in juxtaposition of enhancer elements of immunoglobulin genes IGH, IGK and IGL with MYC on chromosome 8q24 leading to oncogenic MYC overexpression in Burkitt lymphoma and diffuse large B-cell lymphoma. 83,84 In medulloblastoma, somatic structural variants result in placement of growth factor independent 1 family proto-oncogenes, GFI1 or GFI2B, proximal to active enhancers and super-enhancers. 85 Rearrangements of a single oncogenic enhancer on chromosome 3q ectopically activate EVI1 and confer GATA2 functional haploinsufficiency in acute myeloid leukemia.…”