Several lymphoma‐specific genetic events in parallel can be found in mature B‐cell neoplasms

Bacher, Ulrike; Haferlach, Torsten; Alpermann, Tamara; Kern, Wolfgang; Schnittger, Susanne; Haferlach, Claudia

doi:10.1002/gcc.20831

Cited by 34 publications

(38 citation statements)

References 19 publications

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“…Importantly, there are reports of some cases of human B-cell lymphoma possessing concurrent BCL2, MYC and CCND1 translocations. 14,15 Our results strongly support the notion that BCL2, MYC and CCND1 can operate synergistically in the malignant processes related to these cases.…”

Section: Discussionsupporting

confidence: 82%

“…This notion has some credence given that human cases reported to possess BCL2, MYC and CCND1 translocations also harbored additional BCL6 translocations. 14,15 It is important to determine whether BCL6 and/or the other cooperative genes are necessary for human lymphoma formation.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, human B-cell lymphoma cases with concurrent multiple translocations including BCL2, MYC and CCND1 have been reported. 14,15 Given the different biological functions of BCL2, MYC and CCND1, [16][17][18][19][20] we investigated the possibility that these three genes might act synergistically. In vitro assays demonstrated that ectopic expression of all three genes could transform mouse primary B-cells, unlike the cases observed following the expression of any combination of only two of the three genes.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic effect of Bcl2, Myc and Ccnd1 transforms mouse primary B cells into malignant cells

Nakagawa¹,

Tsuzuki²,

Honma³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundA synergistic effect resulting from a combination of BCL2 and MYC or MYC and CCND1 has been implicated in human B-cell lymphomas. Although the identification of other cooperative genes involved is important, our present understanding of such genes remains scant. The objective of this study was to identify the additional cooperative gene(s) associated with BCL2 and MYC or MYC and CCND1. First, we assessed whether Bcl2, Myc and Ccnd1 could cooperate. Next, we developed a synergism-based functional screening method for the identification of other oncogene(s) that act with Bcl2 and Myc. Design and MethodsGrowth in culture, colony formation and oncogenicity in vivo were assessed in mouse primary B cells exogenously expressing various combinations of Bcl2, Myc and Ccnd1. For the functional screening, Bcl2-and Myc-expressing primary B cells were infected with a retroviral cDNA library. Inserted cDNA of transformed cells in culture were then identified. ResultsPrimary B cells exogenously expressing Bcl2, Myc and Ccnd1 showed factor-independent growth ability, enhanced colony-forming capability and aggressive oncogenicity, unlike the cases observed with the expression of any combination of only two of the genes. We identified CCND3 and NRAS as cooperative genes with Bcl2 and Myc through the functional screening. ConclusionsBcl2, Myc and Ccnd1 or Bcl2, Myc and CCND3 synergistically transformed mouse primary B cells into aggressive malignant cells. Our new synergism-based method is useful for the identification of synergistic gene combinations in tumor development, and may expand our systemic understanding of a wide range of cancer-causing elements.Key words: cooperative genes, malignant transformation, oncogenes, Bcl2, Myc, Ccnd1.Citation: Nakagawa M, Tsuzuki S, Honma K, Taguchi O, and Seto M. Synergistic effect of Bcl2, Myc and Ccnd1 transforms mouse primary B cells into malignant cells. Haematologica 2011;96(9):1318-1326. doi:10.3324/haematol.2011 This is an open-access paper.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergistic effect of Bcl2, Myc and Ccnd1 transforms mouse primary B cells into malignant cells

Nakagawa¹,

Tsuzuki²,

Honma³

et al. 2011

Haematologica

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“…13 Lymphomas with MYC, BCL2, and BCL6 rearrangement/translocations, so-called triple-hit lymphoma (THL) are very rare, and only case reports and a few small case series have been published. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] Although one would hypothesize and initial reports suggest that patients with these tumors would be similar to patients with DHL, the available literature is inadequate to support this hypothesis, and it is unknown whether THLs are more like MYC/BCL2 DHLs or MYC/BCL6 DHLs. In addition, the immunophenotype of THL cases is not well characterized.…”

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confidence: 99%

Triple-hit B-cell Lymphoma With MYC, BCL2, and BCL6 Translocations/Rearrangements

Wang

et al. 2015

American Journal of Surgical Pathology

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Lymphomas with translocations/rearrangements of MYC, BCL2, and BCL6, so-called triple-hit B-cell lymphoma, are rare, and few studies on these tumors are available in the literature. We report 11 cases of triple-hit B-cell lymphoma and characterize their clinicopathologic findings. All patients were men, with a median age of 64 years (range, 45 to 80 y), and 4 patients had antecedent or concurrent follicular lymphoma. Using the 2008 World Health Organization classification, these cases were classified as: 5 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma; 4 DLBCL; 1 DLBCL with concurrent follicular lymphoma; and 1 low-grade follicular lymphoma. All cases were positive for CD10, BCL2, and FOXP1. Ten of 11 cases were positive for CD20. MYC expression was high in 10/11 (91%), BCL6 was positive in 8/11 (73%), and MUM1/IRF4 was positive in 6/11 (55%) cases. T-cell antigens, TdT, and Epstein-Barr virus-encoded RNA were negative in all cases. Ten of 11 cases showed a high proliferation index-70% to 100%, and the follicular lymphoma had a 30% proliferation rate. Using most algorithms, all cases belonged to germinal center B-cell-like group. All patients received standard or more aggressive immunochemotherapy regimens. Three patients had no response to chemotherapy; 4 patients showed a partial response; 2 patients had complete remission after chemotherapy; and 2 patients had just begun chemotherapy. Three patients underwent a stem cell transplant. The median follow-up time was 5.3 months. Five patients died, and 6 patients were alive at last follow-up. Two patients who underwent stem cell transplant after complete response to chemotherapy were in remission with 16 to 19 months of clinical follow-up. In summary, triple-hit lymphomas are clinically aggressive tumors associated with a poor prognosis. Patients often respond poorly to chemotherapy, but a subset may completely respond to chemotherapy followed by stem cell transplant.

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“…Patients with MYC/ BCL2 lymphoma can present de novo or be associated with follicular lymphoma. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] The prognosis of patients with MYC/BCL2 lymphomas with de novo disease has been reported, but patients with antecedent/concurrent follicular lymphoma have received less attention in the literature. We also have encountered rare cases of aggressive B-cell lymphoma that carry extra signals of MYC associated with IGH@BCL2 or MYC rearrangement with extra signals of BCL2, and the clinical significance of these molecular combinations is uncertain.…”

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confidence: 99%

B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome

Lin²,

et al. 2012

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B-cell lymphomas with MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also known as double-hit or MYC/BCL2 B-cell lymphomas, are uncommon neoplasms. We report our experience with 60 cases: 52 MYC/ BCL2 B-cell lymphomas and 8 tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals/copies. There were 38 men and 22 women with a median age of 55 years. In all, 10 patients had antecedent/concurrent follicular lymphoma. Using the 2008 World Health Organization classification, there were 33 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (henceforth referred to as unclassifiable, aggressive B-cell lymphoma), 23 diffuse large B-cell lymphoma, 1 follicular lymphoma grade 3B, 1 follicular lymphoma plus diffuse large B-cell lymphoma, 1 B-lymphoblastic lymphoma, and 1 composite diffuse large B-cell lymphoma with B-lymphoblastic lymphoma. Using older classification systems, the 33 unclassifiable, aggressive B-cell lymphomas most closely resembled Burkitt-like lymphoma (n ¼ 24) or atypical Burkitt lymphoma with BCL2 expression (n ¼ 9). Of 48 cases assessed, 47 (98%) had a germinal center B-cell immunophenotype. Patients were treated with standard (n ¼ 23) or more aggressive chemotherapy regimens (n ¼ 34). Adequate follow-up was available for 57 patients: 26 died and 31 were alive. For the 52 patients with MYC/BCL2 lymphoma, the median overall survival was 18.6 months. Patients with antecedent/concurrent follicular lymphoma had median overall survival of 7.8 months. Elevated serum lactate dehydrogenase level, Z2 extranodal sites, bone marrow or central nervous system involvement, and International Prognostic Index 42 were associated with worse overall survival (Po0.05). Morphological features did not correlate with prognosis. Patients with neoplasms characterized by extra MYC signals plus IGH@BCL2 (n ¼ 6) or MYC rearrangement with extra BCL2 signals (n ¼ 2) had overall survival ranging from 1.7 to 49 months, similar to patients with MYC/BCL2 lymphomas. We conclude that MYC/BCL2 lymphomas are clinically aggressive, irrespective of their morphological appearance, with a germinal center B-cell immunophenotype. Tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals, respectively, appear to behave as poorly as MYC/BCL2 lymphomas, possibly expanding the disease spectrum.

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Several lymphoma‐specific genetic events in parallel can be found in mature B‐cell neoplasms

Cited by 34 publications

References 19 publications

Synergistic effect of Bcl2, Myc and Ccnd1 transforms mouse primary B cells into malignant cells

Synergistic effect of Bcl2, Myc and Ccnd1 transforms mouse primary B cells into malignant cells

Triple-hit B-cell Lymphoma With MYC, BCL2, and BCL6 Translocations/Rearrangements

B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome

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