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L. Wang et al.
IGH. In MCL, CCND1 rearrangement is the primary event and MYC-R is likely a secondary event, which is further suggested by the more frequent translocation with IG light chain genes or non-IG genes in our current study. Many oncogenes function by activation mutations or forming oncogenic fusion proteins, however, MYC works differently by loss of tight control of intact MYC at both the transcriptional and translational levels. MYC protein can be upregulated by three major mechanisms, among which MYC translocation and amplification are two of them. This is evidenced by the current findings of signifi- cantly higher level of MYC protein expression and worse OS in the MYC-R MCL group than the two groups with- out MYC-R.
Fifteen patients originally diagnosed with classic variant MCL underwent disease progression/transformation to blastoid/pleomorphic variant of MCL during or after initial treatment. MYC-R was detected at the time of disease transformation in 13 (87%) of these patients, MYC-EC (4- 5 copies) was detected in one patient, and no MYC aberra- tion was detected in one patient. These data suggest that MYC-R is involved in MCL disease progression and trans- formation and also contributed to a poorer prognosis. This finding also confirmed the observation of a few case reports in the literature that described the emergence of MYC-R at time of MCL progression or transformation.24,26,38 Previous studies shown MYC co-operated with transcrip- tionally activated cyclinD1 and resulted in blastoid MCL or oncogenic transformation of B-cell lymphoma in mouse models.5,39 Studies also demonstrated that MYC plays an important role in intrinsic ibrutinib resistance in MCL, pos- sibly by repressing miR15a and miR16-1, two tumor sup- pressor microRNA involved in MCL pathogenesis.40,41 These mechanisms may explain the role of MYC-R in MCL progression or transformation. Of note, secondary MYC translocation is often associated with genomic insta- bility and a complex karyotype. Except activating of MYC, many other factors may also contribute to MCL disease progression and transformation, such as inactivation of CDKN2A and TP53 genes, gain or loss of other chromo- somes and gene mutations. In our current study, all 18 cases of MYC-R MCL with karyotype available showed a complex karyotype, and all nine cases with P53 expression data available showed an over expression of P53 (seven cases with P53 >80% and two cases 50%). These results confirmed the above points. Although only a very small number of progressed or transformed MCL cases were tested for MYC-R by FISH, it is reasonable to conclude that MYC-R is associated with MCL progression or transforma- tion at lease in a subset of MCL patients.
In this study, the MYC protein expression level is signif- icantly higher in MCL with MYC-R than those without MYC-R (MYC>40% in 80% vs. 17% of cases respective- ly). These findings are consistent with previously reported MYC expression in MCL and our previous study of MYC expression in DLBCL.42-44 Our results also demonstrate that using 40% as a cut-off, MYC immunohistochemistry can predict MYC-R with a sensitivity of 80% and a speci- ficity of 83%, better than those reported for DLBCL which has a similar sensitivity but much lower specificity of 61%.44 Based on our results and the aggressiveness of
MCL with MYC-R, we recommend using MYC immuno- histochemistry of >40% as a screening tool to test MYC by FISH in all blastoid/pleomorphic MCL cases for cost effective practice.
A few cases of MCL with MYC-EC have been described in the literature.6,28,45 Yi et al.46 reported 14 patients with MYC-EC and four patients with MYC-R and these 18 patients had a poorer prognosis than a comparison group of MCL patients without MYC abnormalities.46 To date, we are not aware of any prognostic studies for a pure group of MCL patients with MYC-EC without MYC-R. In this study, the prognostic effect of MYC-EC lie in between MYC-NL and MYC-R groups in patients with MCL, simi- lar to the effect of MYC-EC in DLBCL patients.47 Multivariate analysis confirmed that MYC-EC is not a poor prognostic factor in MCL.
MYC/BCL2 DHL is well known as a subset of large B-cell lymphoma with a poor prognosis. Although MCL with MYC-R has been originally suggested as one type of DHL (CCND1 and MYC),20 it has been excluded from the category of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in the 2017 WHO clas- sification, and instead retained in the MCL category. In this study, we compared of these two groups and showed both similarities and differences. Compared with patients with MYC/BCL2 DHL, MCL patients with MYC-R more often presented with bone marrow involvement, Ann Arbor stage IV disease, and more frequent CD5 expres- sion. MCL patients with MYC-R also had a poorer OS, however, this last finding did not hold true in patients with de novo disease. In contrast, elevated serum LDH level and more frequent CD10 and BCL6 expression were more often observed in the MYC/BCL2 DHL group. Overall, these features support the position in the WHO classification that so-called double hit MCL is best kept in the MCL category.
In conclusion, MYC-R is significantly associated with blastoid morphology and CD10 expression in MCL. MCL patients with MYC-R have a very aggressive clinical course and a poor prognosis, similar to patients with MYC/BCL2 DHL and significantly worse than MCL patients without MYC-R. However, the presentation of patients with MCL associated with MYC-R differs from patients with MYC/BCL2 DHL supporting the exclusion of MCL with MYC-R from the category of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. MCL with MYC-EC has a prognostic impact intermediate between patients with MYC-R and patients with normal MYC. These results suggest that MCL patients with different MYC status may need differ- ent treatment strategies. We recommend using MYC immunohistochemistry as a screening tool to test MYC-R by FISH in blastoid/pleomorphic MCL.
Disclosures
No conflicts of interest to disclose.
Contributions
LW, GT, WH and SL performed research; LW and SL per- formed data analysis; LW, GT, LJM, JX, WH, CCY, MW, PJ, PL and SL wrote the manuscript; SL supervised the study.
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