New Mutations in Chronic Lymphocytic Leukemia Identified by Target Enrichment and Deep Sequencing

Doménech, Elena; Gómez‐López, Gonzalo; Gzlez-Peña, Daniel; López, M. García; Herreros, Beatriz; Menezes, Juliane; Gómez‐Lozano, Natalia; Carro, Ángel; Graña, Osvaldo; Pisano, David G.; Domı́nguez, Orlando; García-Marco, José A.; Piris, Miguel Á.; Sánchez‐Beato, Margarita

doi:10.1371/journal.pone.0038158

Cited by 41 publications

(30 citation statements)

References 36 publications

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“…Genes such as BRAF and MLL2 are mutated in CLL and in other B-cell malignancies (13)(14)(15). A few EGR2-and NFKBIE-mutated patients have been reported in CLL (4,5,16). To further establish the importance of the early mutations identified in our patients, we investigated the recurrence of some of them by direct Sanger sequencing of the mutational hotspots of BRAF, EGR2, MED12, MYD88, NFKBIE, NOTCH1, SF3B1, TP53, and XPO1 in the 168 untreated patients with stage B and C CLL who were sampled at inclusion in a clinical trial (www.clinicaltrials.…”

Section: Early Mutations Affect Genes Recurrently Mutated In Cll and mentioning

confidence: 99%

Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

et al. 2014

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Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. SIGNIFICANCE:The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. Cancer Discov; 4(9); 1088-1101

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Section: Early Mutations Affect Genes Recurrently Mutated In Cll and mentioning

confidence: 99%

Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

et al. 2014

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“…Frequent inactivating mutations, including a recurrent 4-bp deletion, of the NFKBIE gene, are seen in advanced stage CLL [73,99,100]. NFKBIE encodes a negative regulator of NFjB signaling in B cells, which is important for controlling the B-cell response to external stimuli, including TLR and BCR signaling [101].…”

Section: Implication Of the Bcr Tlr Pathwaysmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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“…Additional evidence in favor of targeting BCR signaling is found in the mutational studies showing clustering of somatic mutations in genes belonging to pathways involved in BTK downstream effectors, such as those found in PLC/Ca2 + signaling, including PLC, CAMK and NFAT (6 of 105 of the patients analyzed by Quesada et al). 17 This is also supported by the BCR downstream pathway mutations detected in the series by Domenech et al, 44 which affects KRAS, SMARCA2, NFK-BIE and PRKD3, all of which have been shown to play a role in BCR, NF-kB and related signaling pathways. 44 Additionally, members of the MAPK signaling pathway have been found mutated (e.g.…”

Section: Chronic Lymphocytic Leukemiamentioning

confidence: 73%

“…17 This is also supported by the BCR downstream pathway mutations detected in the series by Domenech et al, 44 which affects KRAS, SMARCA2, NFK-BIE and PRKD3, all of which have been shown to play a role in BCR, NF-kB and related signaling pathways. 44 Additionally, members of the MAPK signaling pathway have been found mutated (e.g. EGFR, FGFR2, KRAS, BRAF) 16,17 or with increased mRNA expression (e.g.…”

Section: Chronic Lymphocytic Leukemiamentioning

confidence: 73%

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B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

et al. 2014

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Correspondence: mapiris@humv.es B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nthe high mutational index (MI; number of mutations/megabase (Mb)) of tobacco-associated lung cancer and UV-induced melanoma (MI > 7), to the lower rates for the non-hypermutated form of colorectal carcinoma (MI = 3.2) and breast cancer (MI = 1.4). [26][27][28][29][30][31] Despite there being no established correlation between mutational load and clinical outcome, and considering that the current data have been generated using different NGS platforms, including whole genome (WGS), whole exome (WES) and whole transcriptome (mRNA-seq) approaches, we have compared the mutational index data of B-cell lymphomas obtained from independent NGS studies ( Figure 1 and Table 1) and found that, in general, B-cell lymphomas have a mutational load that is lower than in UV-induced melanomas or tobacco-associated lung cancer, and roughly comparable to that seen in solid tumors in adults. Of the B-cell lymphomas, aggressive B-cell lymphomas (i.e. BL: MI = 4.2; DLCBL: MI = 1.7-3.2) have a higher MI than the other low-grade B-cell lymphomas analyzed (MM, SMLZ, CLL, MCL and HCL: MI ≤ 1). Analyzing the nucleotide substitutions, the rate between transitions (A/G or C/T base changes) versus transversions (C,T/A,G) (Figure 1), we observed that percentage differences between these nucleotide substitutions seem to be more restricted (mostly not exceeding 65% of transitions) in B-cell lymphomas than in the solid tumors induced by tobacco or UV radiation (melanoma > 72%) ( Figure 1 and Table 1).More remarkable results are summarized below. Chronic lymphocytic leukemiaCell survival in chronic lymphocytic leukem...

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New Mutations in Chronic Lymphocytic Leukemia Identified by Target Enrichment and Deep Sequencing

Cited by 41 publications

References 36 publications

Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

Chronic lymphocytic leukemia: Time to go past genomics?

B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

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