Whole-genome sequencing identifies recurrent somatic <i>NOTCH2</i> mutations in splenic marginal zone lymphoma

Kiel, Mark J.; Velusamy, Thirunavukkarasu; Betz, Bryan L.; Zhao, Lili; Weigelin, Helmut G.; Chiang, Mark Y.; Huebner-Chan, David R.; Bailey, Nathanael G.; Yang, David T.; Bhagat, Govind; Miranda, Roberto N.; Bahler, David W.; Medeiros, L. Jeffrey; Lim, Megan S.; Elenitoba-Johnson, Kojo S.J.

doi:10.1084/jem.20120910

Cited by 265 publications

(236 citation statements)

References 47 publications

Supporting

Mentioning

218

Contrasting

Unclassified

Order By: Relevance

“…Similar activating mutations have been recently described in splenic marginal zone lymphomas and in NOTCH1 in aggressive CLL and MCL (37,38). These findings prompted us to expand the study of NOTCH2 and NOTCH1 mutations in MCL and found their presence in 5.2% and 4.7% of the tumors, respectively.…”

Section: Discussionsupporting

confidence: 76%

“…Thus, NOTCH1 mutations have been found in CLL (18,26) whereas NOTCH2 is mutated in splenic marginal zone lymphomas (37,38); however, none of these tumors carry mutations in both NOTCH genes as observed in MCL. In addition, MLL2 and MEF2B mutations are shared with DLBCL (31-33) but are uncommon in CLL, whereas MCL has frequent mutations of ATM and BIRC3 that are also frequent in CLL (39) but uncommon in DLBCL.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

464

361

View full text Add to dashboard Cite

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.next-generation sequencing | cancer genetics | cancer heterogeneity M antle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1 (1). CCND1 is a weak oncogene that requires the cooperation of other oncogenic events to transform lymphoid cells (2). Molecular studies have identified alterations in components of the cell-cycle regulation, DNA damage response, and cell survival pathways (3, 4), but the profile of mutated genes contributing to the pathogenesis of MCL and cooperating with CCND1 is not well defined (1). Most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome with current therapies (5). Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6, 7). This favorable behavior has been associated with IGHV-mutated (8, 9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.To gain insight into the molecular pathogenesis of MCL we performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 29 MCL and further investigated mutated genes in an expanded series of patients. We also analyzed the subclonal heterogeneity of the tumors and their modulation during the evolution of the disease. Results Landscape of Mutations in MCL.We performed WGS and WES of 4 and 29 MCL, respectively. These patients were re...

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

464

361

View full text Add to dashboard Cite

show abstract

“…We conclude that TLR stimulation induces the upregulation of adhesion molecules, which facilitates retention of leukemic cells in a growth-promoting niche. Additionally, within the MZ Cxcr5 ¡/¡ Em-Tcl1 leukemic cells recapitulate some features of human SMZL cells, including susceptibility toward TLR stimulation, upregulation of transcription factors such as NOTCH2 11 and PAX5, 10 upregulation of CD49d 37 and downregulation of CXCR5 expression. 36 In vitro studies showed that the BTK inhibitor Ibrutinib targeted BCR-and chemokine-controlled adhesion and migration 49 and induced a partially VLA-4-dependent adhesion defect.…”

Section: Discussionmentioning

confidence: 73%

“…Notably, activating NOTCH2 mutations have been frequently found in patients with SMZL. 11,46 Because MZ-positioned Cxcr5 ¡/¡ Em-Tcl1 cells concomitantly downregulated IRF4 and upregulated NOTCH2, we propose an alternative explanation for dysregulated NOTCH2 expression. IRF4 does not necessarily act upstream of NOTCH2, but could influence indirectly the localization of B cells in the MZ by altering expression levels of homing receptors.…”

Section: Discussionmentioning

confidence: 86%

“…Pax5 is expressed in SMZL cells and is overexpressed in some SMZL patients due to Pax5 translocations. 10 Notch2 is also frequently mutated in SMZL 11 and is important in the development of MZ B cells. 12 Genes associated with migration and adhesion were also differentially expressed in Cxcr5 ¡/¡ Em-Tcl1 cells, i.e., genes encoding cannabinoid receptor 2 (Cnr2 log 2 fold D 0.7885, p D 0.031) (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

et al. 2017

View full text Add to dashboard Cite

Microenvironmental regulation in lymphoid tissues is essential for the development of chronic lymphocytic leukemia. We identified cellular and molecular factors provided by the splenic marginal zone (MZ), which alter the migratory and adhesive behavior of leukemic cells. We used the Cxcr5 ¡/¡ Em-Tcl1 leukemia mouse model, in which tumor cells are excluded from B cell follicles and instead accumulate within the MZ. Genes involved in MZ B cell development and genes encoding for adhesion molecules were upregulated in MZ-localized Cxcr5 ¡/¡ Em-Tcl1 cells. Likewise, surface expression of the adhesion and homing molecules, CD49d/VLA-4 and CXCR7, and of NOTCH2 was increased. In vitro, exposing Em-Tcl1 cells or human CLL cells to niche-specific stimuli, like B cell receptor-or Toll-like receptor ligands, caused surface expression of these molecules characteristic for a follicular or MZ-like microenvironment, respectively. In vivo, inhibition of VLA-4-mediated adhesion and CXCL13-mediated follicular homing displaced leukemic cells not only from the follicle, but also from the MZ and reduced leukemia progression. We conclude that MZ-specific factors shape the phenotype of leukemic cells and facilitate their niche-specific retention. This strong microenvironmental influence gains pathogenic significance independent from tumor-specific genetic aberrations.

show abstract