MiSTIC, an integrated platform for the analysis of heterogeneity in large tumour transcriptome datasets

Lemieux, Sébastien; Sargeant, Tobias; Laperrière, David; Ismail, Houssam; Boucher, Geneviève; Rozendaal, Marieke; Lavallée, Vincent-Philippe; Ashton‐Beaucage, Dariel; Wilhelm, Brian T.; Hilton, Douglas J.; Mader, Sylvie; Sauvageau, Guy

doi:10.1093/nar/gkx338

Cited by 16 publications

(20 citation statements)

References 62 publications

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“…Table 1). This included well-characterized direct E2 target genes such as GREB1 , XBP1, CTSD , and AGR3 , as well as proliferation-associated genes [30] like E2F1 and MYBL2 (Fig. 1c,d).…”

Section: Resultsmentioning

confidence: 99%

Role of SUMOylation in differential ERα transcriptional repression by tamoxifen and fulvestrant in breast cancer cells

et al. 2018

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Antiestrogens (AEs) are widely used for treatment of estrogen receptor alpha (ERα)-positive breast cancer, but display variable degrees of partial agonism in estrogen target tissues and breast cancer (BC) cells. The fact that BC cells resistant to selective ER modulators (SERMs) like tamoxifen (Tam) can still be sensitive to pure AEs, also called selective ER downregulators, suggests different mechanisms of action, some of which may contribute to the more complete suppression of estrogen target genes by pure AEs. We report herein that pure AEs such as fulvestrant induce transient binding of ERα to DNA, followed by rapid release after 30-40 min without loss of nuclear localization. Loss of DNA binding preceded receptor degradation and was not prevented by proteasome inhibition. Chromatin was less accessible in the presence of fulvestrant than with estradiol or Tam as early as 20 min following treatment, suggesting that chromatin remodeling by pure AEs at ERα target regions prevents transcription in spite of receptor binding. SUMO2/3 marks were detected on chromatin at the peak of ERα binding in cells treated with pure AEs, but not SERMs. Furthermore, decreasing SUMOylation by overexpressing the deSUMOylase SENP1 significantly delayed receptor release from DNA and de-repressed expression of estrogen target genes in the presence of fulvestrant, both in ERα-expressing MCF-7 cells and in transiently transfected ER-negative SK-BR-3 cells. Finally, mutation V534E, identified in a breast metastasis resistant to hormonal therapies, prevented ERα modification and resulted in increased transcriptional activity of estrogen target genes in the presence of fulvestrant in SK-BR-3 cells. Together, our results establish a role for SUMOylation in achieving a more complete transcriptional shut-off of estrogen target genes by pure AEs vs. SERMs in BC cells.

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“…Table 1). This included well-characterized direct E2 target genes such as GREB1 , XBP1, CTSD , and AGR3 , as well as proliferation-associated genes [30] like E2F1 and MYBL2 (Fig. 1c,d).…”

Section: Resultsmentioning

confidence: 99%

Role of SUMOylation in differential ERα transcriptional repression by tamoxifen and fulvestrant in breast cancer cells

et al. 2018

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“…To validate results obtained from bc-GenExMiner database, a cohort from The Cancer Genome Atlas (TCGA) (RNAseq data of 754 breast cancer patients) using MiSTIC software tool [35] and The University of California Santa Cruz (UCSC) Cancer Genomics Browser (gene expression array of 597 patients (AgilentG4502A_07_3 array)) [36] was also used.…”

Section: Methodsmentioning

confidence: 99%

MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis

et al. 2019

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Breast cancer is a heterogeneous disease comprising the estrogen receptor (ER)–positive luminal subtype which is subdivided into luminal A and luminal B and ER-negative breast cancer which includes the triple-negative subtype. This study has four aims: 1) to examine whether Minichromosome Maintenance (MCM)2, MCM4, and MCM6 can be used as markers to differentiate between luminal A and luminal B subtypes; 2) to study whether MCM2, MCM4, and MCM6 are highly expressed in triple-negative breast cancer, as there is an urgent need to search for surrogate markers in this aggressive subtype, for drug development purposes; 3) to compare the prognostic values of these markers in predicting relapse-free survival; and 4) to compare the three approaches used for scoring the protein expression of these markers by immunohistochemistry (IHC). MCM2, MCM4, MCM6, and MKI67 mRNA expression was first studied using in silico analysis of available breast cancer datasets. We next used IHC to evaluate their protein expression on tissue microarrays using three scoring methods. MCM2, MCM4, and MCM6 can help in distinction between luminal A and luminal B whose therapeutic management and clinical outcomes are different. MCM2, MCM4, MCM6, and Ki-67 are highly expressed in breast cancer of high histological grades that comprise clinically aggressive tumors such as luminal B, HER2-positive, and triple-negative subtypes. Low transcript expression of these markers is associated with increased probability of relapse-free survival. A positive relationship exists among the three scoring methods of each of the four markers. An independent validation cohort is needed to confirm their clinical utility.

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“…To identify unique characteristics of triple-mutated AML, we analyzed the mutational landscape of 65 AML samples at diagnosis, which had been subjected to RNA-sequencing (RNA-Seq) as part of the Leucegene Project. [20][21][22][23][24][25] We grouped specimens according to their mutational status of the 3 genes, FLT3-ITD (F), NPM1 (N), and DNMT3A (D), into single-, double-, and triple-mutated samples, and those not mutated in these 3 genes hereafter called "triple wild-type" (WT; Figure 1A; supplemental Table 1). The group of triple-mutated AML samples was further subdivided on the basis of whether the mutation in DNMT3A was located at amino acid position 882 (R882H, R882C) or elsewhere, including missense, point-non-sense, and frameshift mutations (supplemental Table 1).…”

Section: Triple-mutated Aml Samples Are Characterized By An Aberrant mentioning

confidence: 99%

Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML

Garg

Reyes-Palomares

et al. 2019

Blood

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FLT3, DNMT3A, and NPM1 are the most frequently mutated genes in cytogenetically normal acute myeloid leukemia (AML), but little is known about how these mutations synergize upon cooccurrence. Here we show that triple-mutated AML is characterized by high leukemia stem cell (LSC) frequency, an aberrant leukemia-specific GPR56highCD34low immunophenotype, and synergistic upregulation of Hepatic Leukemia Factor (HLF). Cell sorting based on the LSC marker GPR56 allowed isolation of triple-mutated from DNMT3A/NPM1 double-mutated subclones. Moreover, in DNMT3A R882-mutated patients, CpG hypomethylation at the HLF transcription start site correlated with high HLF mRNA expression, which was itself associated with poor survival. Loss of HLF via CRISPR/Cas9 significantly reduced the CD34+GPR56+ LSC compartment of primary human triple-mutated AML cells in serial xenotransplantation assays. HLF knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when reintroduced in culture. RNA sequencing of primary human triple-mutated AML cells after shRNA-mediated HLF knockdown revealed the NOTCH target Hairy and Enhancer of Split 1 (HES1) and the cyclin-dependent kinase inhibitor CDKN1C/p57 as novel targets of HLF, potentially mediating these effects. Overall, our data establish HLF as a novel LSC regulator in this genetically defined high-risk AML subgroup.

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MiSTIC, an integrated platform for the analysis of heterogeneity in large tumour transcriptome datasets

Cited by 16 publications

References 62 publications

Role of SUMOylation in differential ERα transcriptional repression by tamoxifen and fulvestrant in breast cancer cells

Role of SUMOylation in differential ERα transcriptional repression by tamoxifen and fulvestrant in breast cancer cells

MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis

Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML

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