Borderland between DLBCL and Burkitt’s lymphoma -positive lymphomas other than Burkitt’s lymphoma

S.M. Aukema, 1,2 ABSTRACT R. Siebert 1 The history of the so-called “Burkitt Translocation” goes back to 1972 with the description of an additional band at the end of the long arm of 14. Since this discovery, and the subse - 1Institute of Human Genetics, Christian-Albrechts-University Kiel & quent identification of 8q24 as partner and the cloning of the MYC as the involved oncogene, University Hospital Schleswig- MYC translocations were detected in a wide variety of B- and T-cell neoplasms. Also in diagnosing Holstein, Campus Kiel, Germany; MYC translocations there have been major developments, including the introduction of fluorescence 2Department of Pathology & Medical in situ hybridization (FISH). (Molecular) cytogenetic studies have revealed some fundamental differ - Biology, University Medical Center ences between MYC translocations in (BL) and other non-BLs. So in BL, one of the Groningen, Groningen, the three IG -loci is the partner of the MYC locus and the IG -MYC juxtaposition is an initial event in lym - Netherlands phomagenesis. In contrast, in non-BL, MYC translocations can involve a variety of partners and usually represent a late event. Recently, the so-called “double-hit” lymphomas, involving MYC and an accom - panying BCL2 and/or BCL6 translocation, have received increased attention. However, from a genetic Hematology Education: and biological point of view, the distinction between these “double-hit” and MYC “single-hit” lym - the education program for the phomas seems arbitrary as other mechanisms than BCL2 or BCL6 translocation can serve as “first hit”. annual congress of the European Hematology Association 2012;6:195-204 Brief history of MYC -translocations abnormalities in chromosome band 8q24 har - in lymphoma boring the MYC gene “comprise a morphologic The authors own work on the topic is continuum extending from BL to immunoblastic supported by the BMBF (in the The identification of the so-called “Burkitt lymphoma.” 10 Several further cytogenetic and framework of the ICGC MMML-Seq Translocation” goes back to 1972, when, molecular studies lead to the observation that and HaemtoSys Consortia), the Manolov and Manolova, after the introduction aberrations affecting chromosome 8q24 target - Deutsche Krebshilfe and the of banding techniques, described an additional ing the MYC gene can occur in a wide range of Kinderkrebsinitiative band at the end of the long arm of chromo - B-cell lymphomas but in contrast to BL, mostly Buchholz/Holm-Seppensen. S.M.A. is a fellow of the JSM-UMCG MD-PhD some 14 to be recurrent in fresh and cultured constitute changes occurring during disease pro - Burkitt Lymphomas (BLs). 1 In 1976, Zech et gression rather than disease initiation. 11-14 program. We excuse to all our 2 colleagues whose work could not be al. showed that the material added to 14q Consequently, these changes are mostly found included or cited due to space derived from the long arm of chromosome 8 in complex karyotypes and frequently in addi - constraints. through a translocation t(8;14) (q24;q32). tion to well-defined primary chromosomal aber - Finally, after Manolova et al. 3 reported that the rations like the t(14;18). 15-18 translocation was reciprocal, Zhang et al. 4 Moreover, it was shown that besides mapped the translocation breakpoints to sub - involvement of the three immunoglobulin bands 8q24.1 and 14q32. In parallel, the so (IG ) loci in 14q32, 22q11 and 2p12, also non- called “Variant Burkitt Translocations”, IG loci, can be targeted by the aberrations t(8;22)(q24;q11) and t(2;8) (p12;q24) were occurring in lymphomas other than BL. 19-21 described: Berger and coworkers 5 described in Also in the 1980s, it was shown that MYC 1979 the reciprocal translocation between 8q translocations are by far not even specific for and 22q, and the t(2;8) was simultaneously B-cell lymphomas. For example, a rare but described in 1979 in Japan and Belgium by recurrent t(8;14)(q24;q11) involving the locus Miyoshi and coworkers 6 and van den Berghe encoding the T-cell receptor a/δ was identi - and coworkers. 7 The molecular cloning of the fied in T-lineage acute lymphoblastic MYC (previously cellular myc , i.e. , c- myc ) leukemia. 22-26 oncogene was pioneered by Dalla-Favera and The advent of molecular cytogenetic tech - colleagues 8 who showed in 1983 that the MYC niques finally revealed that the MYC onco - locus was recurrently rearranged in “undiffer - gene is targeted by various mechanisms entiated B-cell lymphomas” and that the (including chromosomal translocations) in rearrangements involved a region at the 5’ side cancer in general probably because the pres - of the apparently intact gene. Moreover, these ence of (nearby) fragile and virus integration authors showed that the rearrangements recur - sites. 27,28 Finally, polymorphic sites at various rently involved immunoglobulin heavy chain distances to the MYC locus are also associated (IGH ) mu sequences on chromosome 14. 9 with germline predisposition to various can - Despite having been identified and being cers although whether, and if so by what strongly associated with BL, in the early 1980s, mechanisms, they target MYC (expression) it was shown that malignant lymphomas with remains to be further elucidated. 29-34

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eral hundred kilobases on both sides of the MYC Diagnosing MYC -translocations: lessons from locus. 47,48,50,51 This molecular heterogeneity hampers PCR- molecular genetics based methods, though some LDI-PCR based approaches As described above, chromosome banding analysis was have been successfully applied at least for the IG -MYC the initial method to diagnose chromosome 8q24 aberra - translocations. 51 For Southern blot, in addition, consider - tions suggestive for MYC -involvement. Still metaphase able amounts of high quality DNA are needed, which in karyotyping is the recommended technique if leukemic or many instances is not available. other fluid tumor compartments can be obtained because Nowadays, the most widely applied technique to diag - it can give a genome-wide or so-called “Bird’s eye” nose MYC translocation is fluoresence-in-situ- overview on primary and secondary chromosomal hybridization (FISH). 53 Usually, break-apart probes are changes. 15,35 Nevertheless, chromosome banding is a labo - applied that use differently labeled probes flanking the rious technique and not applicable to fixed specimens. MYC locus. A variety of commercially available break- Moreover, particularly in case of complex aberrations, apart probes is currently available from various suppliers. chromosome banding can miss aberrations involving Nevertheless, caution has to be warranted here as the 8q24 or fail to identify the MYC partner. 36 Additionally, probes have different designs and fluorescent labels and conventional cytogenetics is not suitable to diagnose flank different parts of the MYC locus (for a detailed small insertions of IG sequences into the MYC locus or of overview of the positions of different MYC probes rela - small insertion of MYC anywhere in the genome. 37-39 The tive to the MYC locus, see Put et al. 14 supplementary peculiarities of the translocations affecting the MYC locus data). 38 Due to the scattering of the breakpoints (Table 1), render also classical molecular techniques not really suit - a reliable exclusion of MYC breaks is only possible if the able for diagnostic use. Activation of MYC takes place on region flanked by the respective break-apart probe is of the der(14) in t(8;14) and on the der(8) in t(2;8) and sufficient size. In turn, this renders the problem that such t(8;22) and most non- IG -MYC translocations. 40-44 In con - probes also show some splitting in normal cells. Thus, the sequence, the breakpoints on the der(8) differ between the cut-offs for the detection need to be carefully established. t(8;14) and its variants being telomeric to the MYC gene Probes flanking a smaller region around the MYC locus in the latter and in the 5’ part or centromeric of MYC in show less splitting in normal cells but might miss some of the prior. 45-52 Moreover, breakpoints can scatter over sev - the MYC translocations. In particular, far 5’ breaks (cen -

Table 1. MYC translocations, breakpoint location and partner in lymphoma.

Translocation Locations of breakpoint in MYC Partner gene Disease/Primary aberrations References t(8;14)(q24;q32) class I: EXON-I, INTRON-I IGH sporadic BL, endemic BL, HIV+ BL 45-48 class II: 5’ EXON-I class III: far 5’ EXON-I t(8;14;12)(q24;q32;24) EXON-I - EXON-II, 5’ of der(8) IGH, BCL7A BL 146 t(8;14)(q24;q11) 3’ TCRA/D T-ALL 22-26 t(2;8)(p12;q24) (far) 3’ IGK BL (primary event) 50-52 other: secondary event t(8;22)(q24;q11) (far) 3’ IGL BL (primary event) 49,50 other: secondary event t(8;9)(q24;p13) 3’ a Centromeric of PAX5 b DLBCL, BCLU 55,97,147,148 t(3;8)(q27;q24) 3’ BCL6 DLBCL 98,149 t(8;12)(q24;p12.1) 3’ LRMP DLBCL / BCLU 150 t(8;12)(q24;q22) 3’ BTG1 B-CLL c 21 t(8;17)(q24;q25) INTRON-1 ALO17 ALK(+) ALCL 151 t(8;17)(q24;q22) EXON-1 “BCL3 ”d B-APL 19 t(2;8)(q34;q24) 3’ TCL4 e TCL 20 aGenomic breakpoint localization not available in one additional case, which was mapped by FISH to a region of 85 kb encompassing MYC; 97 bbreakpoints at 9p13 are located in a region up to several hundred kilobase pairs centromeric of PAX5 55,97,147,148 and may or may not involve PAX5 ;147,148 cB-CLL with t(11;14)(q13;q32) in blastic transformation, likely representing a MCL; dthe gene on 17q was by the authors assigned “ BCL3 ” in the original publication. However, this should not be confounded with the gene on chromosome 19, which is nowadays referred to as BCL3 ; epatient suffering from Sézary’s syndrome. Abbreviations (not mentioned elsewhere in text); BCLU, B-cell lymphoma unclassifiable; ALK+ ALCL, anaplastic lymphoma kinase positive anaplastic large cell lymphoma; B-APL, B-cell acute prolymphocytic leukemia; TCL, T-cell leukemia. For the full gene names, we refer to the original manuscripts.

| 196 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) Amsterdam, The Netherlands, June 14-17, 2012 tromeric of MYC ) occurring in a subset of IGH -MYC pered by the wide variation in different techniques used to translocations might be of relevance here. 47 To this end, an determine gains 64,66,69,71-76 and the effect on MYC expression IGH -MYC double color double fusion probe should level. 64,66,72-74 always be combined with a break-apart probe to detect such far breakpoints. In addition, such a probe picks up the majority of insertions of IGH into MYC or vice versa, What distinguishes other MYC -positive which can be missed by a MYC break apart probe. 38,53 lymphomas from Burkitt lymphoma? Finally, it needs to be emphasized that as detailed below, the definition of the MYC translocation partner can be of The characteristic difference between BL and other some diagnostic help. Here, double-color double fusion MYC -positive lymphomas (with the notable exception of probes of MYC and the candidate partners are recom - TCR -MYC positive T-ALL) is the fact that in BL, the IG - mended. 50,54 Break-apart probes of the potential partners MYC translocation is supposed to be an initial ( i.e. , pri - are not sufficient to our experience as they do even in the mary) event (Figure 1). 60 Similarly, in T-ALL, the TCR - case of a positive splitting event do not reliably identify MYC translocation is supposed to be an initial event. 60 In the partner. This can have diagnostic and clinical conse - contrast, in all other lymphomas, MYC translocation quences considering, for example, a break in the MYC occurs during clonal evolution of the disease usually as a and the IGL locus could be due to a t(8;22)/ IGL -MYC late event. 11-14 fusion ( i.e. , a single-hit compatible with BL) or a This view is supported by the fact that in BL the t(8;14) t(22;oncogene) and t(partner; MYC ) translocation ( i.e. , a and variants typically occur in a rather simple karyotype double-hit). 55,56 It can be expected that in the future the and there is evidence that a complex karyotype in a typical technique of choice could become full genome sequenc - BL indicates disease progression. 15,54,77-79 Moreover, the pat - ing, which at the same time can detect all translocations tern of secondary changes in BL is restricted with 40% of and insertions of MYC , as well as MYC mutations present the BL lacking cytogenetically detectable secondary in some BL. changes. 15 In the others, gains at 1q, 7 and 12 The molecular consequence of the 8q24 translocation is are the most common. 15 Moreover, recent observations from deregulation of the MYC oncogene at 8q24 through juxta - next generation sequencing suggest that BL harbor, in addi - position next to regulatory elements of another locus. For tion to the IG -MYC translocation, a peculiar set of mutations details on the pathogenic consequences of MYC activa - probably targeting defined pathways potentially necessary tion, the reader is referred to recently published, excellent to allow IG -MYC positive cells to transform rather than to reviews on these topics. 57-61 This activation of the MYC undergo apoptosis. 80,81 (and own unpublished data). offers the opportunity for an alternative approach As outlined above, in B-cell lymphomas other than BL the to detect or predict the presence of a MYC translocation occurrence of MYC -translocation is supposed to be a second - namely by immunohistochemistry (IHC) using antibodies ary event occurring in an already malignant clone. The pri - against the MYC protein. Using a novel monoclonal anti - mary hits driving such a malignant clone can be heteroge - body against MYC , Ruzinova et al. found that a nuclear neous. Despite this fact, it has been proposed to distinguish (or mixed nuclear/cytoplasmic) staining pattern correlat - between so-called “double-hit” lymphomas and other MYC ed with the presence of a MYC translocation while many positive lymphomas. “Double hit” is usually defined as other lymphomas, lacking a MYC translocation, had a pri - MYC -translocation in addition to an IGH -BCL2 transloca - marily cytoplasmic staining pattern. 62 However, this has tion and/or a BCL6 breakpoint. We believe that this defini - not been confirmed by others. 63-65 Three recent reports, tion of “double hit” is biologically meaningless due to vari - using a MYC (two) and VpreB3 (one) antibody, respec - ous reasons (Figure 1): tively showed that these stainings might be helpful in the 1) Numerous oncogenes can, in the absence or presence identification of lymphomas “at risk” for carrying a MYC of an accompanying MYC break, be activated through translocation and therefore candidates for additional juxtaposition to an IG -locus in B-cell lymphoma. genetic evaluation. 64-66 Immunophenotypical characteris - Besides t(14;18)(q32;q21)/ BCL2 -IGH and t(3;14) tics, including a high Ki67 proliferation rate or a germinal (q27;q32)/ BCL6 -IGH , this can be, for example, the center (GCB) phenotype, have been associated with the t(11;14)(q13;32)/ CCND1 -IGH in mantle cell lym - presence of a MYC translocation in some individual stud - phoma. Other well-known oncogene partners of IG ies but are not considered reliable markers for the detec - loci in B-cell lymphomas are, for example, BCL10 , tion of MYC rearrangements in DLBCL. The recommen - MALT1 , CCND2 and 3, or CCNE1 .82 Biologically, dation of many authors is to screen all DLBCL and/or there seems not to be a difference whether MYC DLBCL-BL intermediates for MYC rearrangements in occurs in a clone driven by BCL2 or BCL6 or in a diagnostic workup. 67-71 clone driven by one of the other named oncogenes While over the last years the knowledge about MYC (though the latter might be much more rare). Indeed, translocations in B-cell lymphomas has dramatically we have recently extended the definition of “double- expanded, less attention has been paid to another type of hit” lymphoma by identifying 9p13/ MYC +, chromosomal aberration that can be detected by FISH, BCL3 +/MYC + and CCND1 +/ MYC + as novel “double- namely MYC gains. Various biological and clinical hit” combinations as they were recurrent within the aspects, including gene/protein dosage effects, as well as group of MYC “single-hit” ( i.e. BCL2 -/ BCL6 -/ MYC +) prognostic impact, could be a challenging subject of fur - B-cell lymphomas. 83 Clinically, the course seems to be ther investigation. However, for both the effect on MYC worse in all of these “double-hits”, though the number expression (mRNA/protein) 64,66,72-74 and the prognostic of cases described with primary hits affecting partners impact, 69,71-76 obtained results are heterogeneous so far, and other than BCL2 or BCL6 is still low simply because a straightforward comparison of different studies is ham - the incidence of these translocations is low. From the

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point of classification, considering that around half of all ABC-type DLBCL are supposed to have illegiti - mate IGH -rearrangements, 84 it seems difficult to understand why BCL2 and BCL6 break positive cases should be distinguished from other IGH translocation positives. 2) An oncogene can be hit for activation by various means being translocation only one of them. For example, BCL6 can be deregulated by translocation, mutation, and gain. Classifying only BCL6 translocat - ed cases but not BCL6 mutated or gained cases with MYC break as “double-hits” would contradict the dif - ferent cellular mechanisms of oncogene activation (Figure 2). In essence, all these mechanisms can lead to BCL6 protein deregulation, which is the functional read-out of the “hit”. 3) Recent next generation sequencing data suggest that the mutational landscape of B-cell lymphomas is much more excessive than probably suggested simply by cytogenetics. These studies identified in DLBCL and Figure 1. Genetic model for MYC induced lymphomagene - FL at clinical presentation a total number of approxi - sis in Burkitt lymphoma (BL) and MYC positive lymphoma mately 100 (recurrently) mutated genes. 85,86 Thus, all of other than BL. In BL, the IG -MYC translocation is an initial event and is accompanied by no or few secondary genomic them contain multiple cancerous hits in addition to or aberrations resulting in a low genomic complexity. On the despite lacking a BCL2 and/or BCL6 break. other hand, in the other MYC positive lymphomas the IG - Based on these reasons we propose to simply distin - MYC or non- IG -MYC translocation is a late event often MYC involved in disease progression or high-grade transforma - guish between B-cell lymphomas in which translo - tion. The initial hits in these lymphomas consist of IG - cation is an initial event ( i.e. , BL, probably some few translocation involving oncogenes other than MYC (IG -X), CLL) and those in which MYC translocations appear dur - genomic imbalances, mutations or more likely a combina - ing disease progression ( i.e. , all other B-cell lymphomas). tion of these. So here, the MYC translocation occurs in the context of a much more complex genomic background as In a given case, indicators of MYC translocation being a is the case in BL and results in a much higher genomic late event are, in addition to histology and age, a complex complexity. (Figure modified from Salaverria & Siebert). 104 karyotype, and non- IG -MYC partners. 11,15,54,78 With few exceptions, MYC translocation as late event identifies a poor prognosis in a given disease group. 11,13,14,37,54,67,68,70,87,88

MYC -positive B-Cell lymphomas other than Burkitt lymphomas

The following section and Table 2 give an overview on MYC translocations in B-cell lymphomas other than BL. Diffuse large B-cell lymphoma and “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma” In diffuse large B-cell lymphoma (DLBCL), the fre - quency of MYC rearrangements varies between 3 and 16%. 54,67,68,70,71,76,87,89-91 However, due to the high incidence of DLBCL (30-40% of all NHL) as compared with BL, the absolute number of MYC breaks in DLBCL will outnum - ber that of BL. In contrast to BL with approximately 85% of the cases having an IGH -MYC breakpoint, the partners of MYC are more diverse, including the IG -light chain genes, as well as non- IG genes. 15,18,54 A group lymphomas in which MYC translocations occur more frequently are the lymphomas included in the 2008 WHO classification “B-cell lymphoma, unclassifiable, with features interme - diate between diffuse large B-cell lymphoma and Burkitt lymphoma”, hereafter abbreviated as DLBCL/BL. This Figure 2. Current concept of BCL6 +/MYC + double hit lym - 69,92 phoma. The current definition for “double-hit” lymphoma percentage varies between 30 and 55%. Interestingly, does not “acknowledge” the combination of BCL6 muta - in 20-80% of the DLBCL and DLBCL/BL with a MYC tions and/or gains as “double-hit” lymphoma. However, breakpoint, there is an accompanying BCL2 and/or BCL6 this distinction seems arbitrarily as other mechanisms, for 160 67-71,76,89,91,93-96 example, BCL6 (activating) mutations, may result in breakpoint. These cases are referred to as deregulated BCL6 expression. “double” and “triple” hit lymphomas. 83,92 In the case of

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MYC -BCL6 DHs, BCL6 itself may be involved as MYC reported for FL3B, with or without DLBCL component, partner in a t(3;8)(q27;q24). 97,98 Overall these DH and THs or those with blastoid features. 110,111,116 Of note, certainly account for approximately 1-12% of all DLBCL not all MYC + FL are BCL2 +/MYC + DHs, as some FL (espe - cases. 67,70,71,76,89,91 The picture is strikingly different in pedi - cially the FL3B, with or without DLBCL component) atric DLBCL, in which the frequency of MYC rearrange - may lack the t(14;18) and represent instead MYC + “single- ments is high and double hits are extremely rare to hits” or BCL6 +/MYC + DHs. 110 absent. 99-102 Both the fact that many pediatric MYC posi - tive DLBCL may in fact represent BL at the molecular Primary mediastinal B-cell lymphoma and level and the virtual absence of the t(14;18) in pediatric Hodgkin lymphoma DLBCL may contribute to this. 101,103 For further details on In (pediatric) PMBCL, MYC rearrangements are rare the morphologic, epidemiologic, clinical, and gene events but do occur. 117,118 In Hodgkin lymphoma (HL), this expression aspects in the grey zone between BL and MYC seems also be the case. 119 In the recently introduced “B- positive DLBCL including intermediate lymphomas, the cell lymphoma, unclassifiable, with features intermediate reader is referred to a recent review by us. 104 between diffuse large B-cell lymphoma and classical Hodgkin lymphoma”, MYC rearrangements have not been Follicular lymphoma detected so far and, as in HL, MYC gains were frequently Acquisition of MYC rearrangements by t(14;18)+ FL present. 120,121 However, MYC rearrangements are rarely (or its t(14;18)+ progenitors) has shown to result in trans - investigated in HL, making comparison with the newly formation to aggressive pre-B-cell lymphoblastic, plas - introduced gray zone lymphomas difficult. mablastic, and Burkitt-like lymphoma. 13,105-109 From a tumor biology perspective, it is interesting to see whether, Chronic lymphocytic leukemia (CLL) and if so, at what frequency MYC translocations occur in MYC rearrangements in B-cell CLL (and formerly B- morphologically untransformed FL. Studies systematical - PLL) have shown to be an extremely rare event. The fre - ly assessing the frequency of MYC rearrangements in quency is (estimated) to be well below 1%. 14,88,122 In the pediatric and adult FL show that they do occur and report majority of the cases MYC has an IG partner. 14 The pres - a frequency of 0-12%. 110-114 In unselected series, MYC ence of a MYC translocation in CLL and PLL is associat - rearrangements seem to be absent to rare in low grade ed with aggressive disease and poor survival. 14,88 (grade 1-2) FL 110,113,115 while higher incidences have been Nevertheless, our observations suggest that probably also

Table 2. Overview on chromosomal aberrations affecting the MYC locus in various lymphoma entities.

Lymphoma MYC partner Frequency of MYC rearrangement (%) DH lymphoma? References

MYC as primary hit Burkitt IG -MYC IGH >> IGL /IGK likely ≈100 NO 15,152,153 T-ALL TCR A/D 1-3 NO 154-157

MYC as secondary hit FL IG -MYC 0-12 a BCL2 +/MYC + DH 110,112-114 non- IG -MYC BCL6 +/MYC + DH BCL2 +/BCL6 +/MYC + TH

MCL IG -MYC ≈5b CCND1 +/MYC + DH 37,123-129,158 non- IG -MYC

B-CLL / B- PLL IG -MYC ; non- IG -MYC IG -MYC > non- IG -MYC <1 NO 14,88,122

MM IG -MYC ; non- IG -MYC often complex rearrangements 15-50 NO c 39,131-133

PBL IG -MYC ; non- IG -MYC IG -MYC >> non- IG -MYC 33-60 rare - absent 137,138,159

DLBCL IG -MYC ; non- IG -MYC IGH , IGK/L & various (recurrent) 3-16 BCL2 +/MYC + DH 54,67,68,71,76,89-91,97,98 non- IG partners BCL6 +/MYC + DH BCL2 +/BCL6 +/MYC + TH

pediatric DLBCL IG -MYC 7-35 d (extremely) rare - absent 99-102,152

DLBCL/BL IG -MYC non- IG -MYC common 30-55 e BCL2 +/MYC + DH 69,92 non- IG -MYC BCL6 +/MYC + DH BCL2 +/BCL6 +/MYC + TH aMay vary across different FL grades, observed in 15 to 22% of FL3b; 110,116 b8q24 aberrations in conventional cytogenetics; 83 cthe combination of the t(11;14) and MYC translocations does occur in MM but are not referred to as DH; 83 dfor Deffenbacher et al. 152 the (%) MYC breaks in lymphomas with a molecular diagnosis of DLBCL is given. For Klapper et al. 101 (%) given is for lymphomas with a non-mBL signature (the molecular counterpart of morphologic/histopathologic DLBCL). 101,104 This is higher in lymphomas with an intermediate signature (44%); e78% in Foot et al. 96 in which any DH lymphoma was classified as DLBCL/BL intermediate.

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 199 | 17 th Congress of the European Hematology Association quite indolent cases of IG -MYC positive CLL do exist is not confined to cases with a MYC translocation 140,141 and (Siebert et al. , unpublished data). high MYC expression (or activity as measured by gene expression signatures) can be found in various B-cell neo - Mantle cell lymphoma plasms, including MCL, 142,143 multiple myeloma, 144 and Recently the definition of “double-hit lymphoma” has DLBCL .140,141,145 And, moreover, in several of these publi - been extended to lymphomas having both CCND1 and cations, high MYC expression was associated with a poor MYC breakpoints 83 and approximately 5% of all prognosis. Therefore, it could, both from a biological and t(11;14)(q13;q32)+ MCLs in the Mitelman database of clinical perspective, be interesting to broaden the focus. chromosome aberrations in cancer was shown to have an It should also be noticed that the optimal clinical man - additional 8q24 breakpoint. Most, but not all, 123 of these agement of MYC -positive lymphomas other than BL, here “double-hit” lymphomas had blastic / pleomorphic blas - with emphasis on the DLBCL and DLBCL/BL intermedi - toid 12,37,124-128 or even Burkitt-like morphology. 37,129 ates, given their frequent occurrence in combination with “Double-hit” mantle cell lymphoma seems to run an their poor prognostic impact, 54,67-70,87 represent a major clin - aggressive course with the average survival being 8 ical challenge. months only. 37 Finally, it is to be expected that application of next gen - eration sequencing will provide, with the identification of Plasma cell neoplasms novel recurrent mutations, new insights to the pathogene - The plasma cell neoplasms in the 2008 WHO classifi - sis of MYC -positive lymphomas and will show both novel cation include, amongst others, monoclonal gammopathy molecular similarities, as well as differences among them. of undetermined significance (MGUS), plasma cell myeloma, and plasma cell leukemia (PCL). 130 In plasma cell myeloma, MYC rearrangements can be found in 15- References 50% of (advanced) tumors and in even up to approximate - ly 90% of myeloma cell lines, and these rearrangements 1. Manolov G, Manolova Y. Marker band in one chromosome 14 from Burkitt lymphomas. Nature 1972; 237(5349): 33-4. appear late in the course of MM and are considered to be 2. Zech L, Haglund U, Nilsson K, Klein G. Characteristic chro - associated with tumor progression. 39,131-133 Among the IG mosomal abnormalities in biopsies and lymphoid-cell lines translocations in MM are also the t(8;14)(q24;q32) and from patients with Burkitt and non-Burkitt lymphomas. Int J variants involving the MYC gene. 131,134 They comprise Cancer 1976; 17(1): 47-56. 39,131,132 3. Manolova Y, Manolov G, Kieler J, Levan A, Klein G. Genesis about 10-15% of the MYC aberrations in MM. It is of the 14q+ marker in Burkitt’s lymphoma. Hereditas 1979; worthy to notice that 8q24 aberrations are highly hetero - 90(1): 5-10. geneous in terms of the breakpoint locations. 135 4. Zhang S, Zech L, Klein G. High-resolution analysis of chro - mosome markers in Burkitt lymphoma cell lines. Int J Cancer 1982; 29(2): 153-7. Plasmablastic lymphoma 5. Berger R, Bernheim A, Weh HJ, Flandrin G, Daniel MT, Plasmablastic lymphoma (PBL), on the other hand, is Brouet JC, et al. A new translocation in Burkitt’s tumor cells. 136 Hum Genet 1979; 53(1): 111-2. an extremely rare and separate disease entity and has 6. Miyoshi I, Hiraki S, Kimura I, Miyamoto K, Sato J. 2/8 been strongly associated with immunodeficient condi - translocation in a Japanese Burkitt’s lymphoma. Experientia tions, including infection with the HIV virus and 1979; 35(6): 742-3. immunosuppressive therapy to avoid allograft rejection 7. Van Den Berghe H, Louwagie A, Broeckaert-Van Orshoven A, David G, Verwilghen R, Michaux JL, et al. Philadelphia chro - after transplantation. MYC rearrangements, most com - mosome in human multiple myeloma. J Natl Cancer Inst 1979; monly IGH -MYC , have a high incidence (50-60%) and 63(1): 11-6. may in (extremely) rare occasions be accompanied by 8. 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