Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

Wang, Lili; Shalek, Alex K.; Lawrence, Mike; Ding, Ruihua; Gaublomme, Jellert T.; Pochet, Nathalie; Stojanov, Petar; Sougnez, Carrie; Shukla, Sachet A.; Stevenson, Kristen E.; Zhang, Wandi; Wong, Jennifer; Sievers, Quinlan L.; MacDonald, Bryan T.; Vartanov, Alexander R.; Goldstein, Natalie R.; Neuberg, Donna; He, Xi; Lander, Eric S.; Hacohen, Nir; Regev, Aviv; Getz, Gad; Brown, Jennifer R.; Park, Hongkun; Wu, Catherine J.

doi:10.1182/blood-2014-01-552067

Cited by 69 publications

(57 citation statements)

References 37 publications

(64 reference statements)

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“…The functional role of several putative driver mutations has been confirmed; for example, silencing mutated WNT pathway genes in primary CLL cells resulted in decreased cell viability 47 . Mutations in POT1 , which has a role in the protection of telomeres, prevented the binding of protection of telomeres protein 1 to telomeric DNA, resulting in numerous chromosomal abnormalities, in addition to the development of abnormal telomeres.…”

Section: Mechanisms/pathophysiologymentioning

confidence: 96%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

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Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

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Section: Mechanisms/pathophysiologymentioning

confidence: 96%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

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411

437

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“…Analysis of an independent DLBCL cohort from The Cancer Genome Atlas confirmed that 78% of individual DLBCL samples had upregulated mRNA expression of genes from IEGS. The analysis of additional cohorts from other cancers evidenced an individual variation of IEGS expression among patients with chronic lymphocytic leukemia (CLL) (NCBI GEO data set GSE31048 32 ), and no significant upregulation of the IEGS in samples from multiple myeloma patients (NCBI GEO dataset GSE6691 33 ) (Fig. 1F).…”

Section: Fl and Dlbcl Upregulate The Expression Of Immune Escape Genesmentioning

confidence: 99%

“…1E), the random distribution of ECDF of IEGS was tested by one-sample KS test. The same procedure was applied to other samples of NHL 30 : ABC and GC samples of DLBCL from the study GSE12195, 29 MM samples of the study GSE6691 33 and CLL samples of the study GSE31048 32 (ECDFs shown in red, Fig. 1F).…”

Section: Ks Tests For Iegs Distribution Analysismentioning

confidence: 99%

Several immune escape patterns in non-Hodgkin's lymphomas

et al. 2015

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Follicular Lymphomas (FL) and diffuse large B cell lymphomas (DLBCL) must evolve some immune escape strategy to develop from lymphoid organs, but their immune evasion pathways remain poorly characterized. We investigated this issue by transcriptome data mining and immunohistochemistry (IHC) of FL and DLBCL lymphoma biopsies. A set of genes involved in cancer immune-evasion pathways (Immune Escape Gene Set, IEGS) was defined and the distribution of the expression levels of these genes was compared in FL, DLBCL and normal B cell transcriptomes downloaded from the GEO database. The whole IEGS was significantly upregulated in all the lymphoma samples but not in B cells or other control tissues, as shown by the overexpression of the PD-1, PD-L1, PD-L2 and LAG3 genes. Tissue microarray immunostainings for PD-1, PD-L1, PD-L2 and LAG3 proteins on additional biopsies from 27 FL and 27 DLBCL patients confirmed the expression of these proteins. The immune infiltrates were more abundant in FL than DLBCL samples, and the microenvironment of FL comprised higher rates of PD-1 C lymphocytes. Further, DLBCL tumor cells comprised a higher proportion of PD-1C, PD-L1 C , PD-L2C and LAG3 C lymphoma cells than the FL tumor cells, confirming that DLBCL mount immune escape strategies distinct from FL. In addition, some cases of DLBCL had tumor cells co-expressing both PD-1, PD-L1 and PD-L2. Among the DLBCLs, the activated B cell (ABC) subtype comprised more PD-L1C and PD-L2 C lymphoma cells than the GC subtype. Thus, we infer that FL and DLBCL evolved several pathways of immune escape.

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“…[24] The canonical Wnt pathway controls intracellular levels of β-catenin, a protein independently involved in cell adhesion and co-transcriptional activity for Wnt signal transduction [25,26] Dysregulation of the Wnt pathway has been heavily implicated in multiple human diseases, especially in cancers such as colorectal cancer, [27] chronic lymphocyte leukemia [28], gastric cancer [29], hepatocellular cancer [30], prostate cancer [24, 31], and breast cancer [24,31]. In ovarian cancer, activation of the Wnt pathway plays an important role in ovarian cancer chemoresistance to drugs such as cisplatin.…”

Section: Discussionmentioning

confidence: 99%

High Expression of miR-532-5p, a Tumor Suppressor, Leads to Better Prognosis in Ovarian Cancer Both In Vivo and In Vitro

Wang

Chang

Kao

et al. 2016

Molecular Cancer Therapeutics

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Ovarian cancer is the leading cause of death for gynaecological cancers, ranking fifth overall for cancer-related death among women. The identification of biomarkers and the elucidation of molecular mechanisms for improving treatment options have received extensive efforts in ovarian cancer research. MicroRNAs (miRNAs) have high potential to act as both ovarian cancer biomarkers and as critical regulators of ovarian tumor behavior. We comprehensively analyzed global messenger RNA (mRNA), miRNA expression, and survival data for ovarian cancer from the Cancer Genome Atlas (TCGA) to pinpoint miRNAs that play critical roles in ovarian cancer survival through their effect on mRNA expression. We performed miRNA overexpression and gene knockdown experiments to confirm mechanisms predicted in our bioinformatics approach. We established that overexpression of miR-532-5p in OVCAR-3 cells resulted in a significant decrease in cell viability over a 96-hour time period. In the TCGA ovarian cancer data set, we found 67 genes whose expression levels were negatively correlated with miR-532-5p expression and correlated with patient survival, such as WNT9A, CSNK2A2, CHD4, and SH3PXD2A. The potential miR-532-5p-regulated gene targets were found to be enriched in the Wnt pathway. Overexpression of miR-532-5p through miRNA mimic caused downregulation of CSNK2A2, CHD4, and SH3PXD2A in the OVCAR-3 cell line. We have discovered and validated the tumor-suppressing capabilities of miR-532-5p both in vivo through TCGA analysis and in vitro through ovarian cancer cell lines. Our work highlights the potential clinical importance of miR-532-5p expression in ovarian cancer patients.

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Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

Abstract: Key Points Wnt pathway is frequently mutated in CLL. Wnt pathway mutations can lead to pathway activation and enhanced CLL survival.

Cited by 69 publications

References 37 publications

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia

Several immune escape patterns in non-Hodgkin's lymphomas

High Expression of miR-532-5p, a Tumor Suppressor, Leads to Better Prognosis in Ovarian Cancer Both In Vivo and In Vitro

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