Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: FES (cancer-related)
BACKGROUND: Expression of the microRNA miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA or oncomir. Due to the critical functions of its target proteins in various signaling pathways, miR-21 is an attractive target for genetic and pharmacological modulation in various cancers. Cervical cancer is the second most common cause of death from cancer in women worldwide and persistent HPV infection is the main etiologic agent. This malignancy merits special attention for the development of new treatment strategies. In the present study we analyze the role of miR-21 in cervical cancer cells.
METHODS: To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression in a cervical intraepithelial neoplasia-derived cell lines using siRNAs. The effect of miR-21 on gene expression was assessed in cervical cancer cells transfected with the siRNA expression plasmid pSIMIR21. We identified the tumor suppressor gene PTEN as a target of miR-21 and determined the mechanism of its regulation throughout reporter construct plasmids. Using this model, we analyzed the expression of miR-21 and PTEN as well as functional effects such as autophagy and apoptosis induction.
RESULTS: In SiHa cells, there was an inverse correlation between miR-21 expression and PTEN mRNA level as well as PTEN protein expression in cervical cancer cells. Transfection with the pSIMIR21 plasmid increased luciferase reporter activity in construct plasmids containing the PTEN-3'-UTR microRNA response elements MRE21-1 and MRE21-2. The role of miR-21 in cell proliferation was also analyzed in SiHa and HeLa cells transfected with the pSIMIR21 plasmid, and tumor cells exhibited markedly reduced cell proliferation along with autophagy and apoptosis induction.
CONCLUSIONS: We conclude that miR-21 post-transcriptionally down-regulates the expression of PTEN to promote cell proliferation and cervical cancer cell survival. Therefore, it may be a potential therapeutic target in gene therapy for cervical cancer.
BACKGROUND: Aberrant activation of the Wnt/β-catenin pathway is a major and frequent event in liver cancer, but inhibition of oncogenic β-catenin signaling has proven challenging. The identification of genes that are synthetically lethal in β-catenin-activated cancer cells would provide new targets for therapeutic drug design.
METHODS: We transfected the parental HuH6 hepatoblastoma cell line with a doxycycline-inducible shRNA against CTNNB1 (gene coding for β-catenin) to obtain an isogenic cell line pair with or without aberrant β-catenin signaling. Using this hepatoblastoma isogenic cell line pair, we performed a human kinome-wide siRNA screen to identify synthetic lethal interactions with oncogenic CTNNB1. The phenotypic readouts of the screen were cell proliferation, cell cycle arrest and apoptosis, which were assessed by image-based analysis. In addition, apoptosis was assessed by flow cytometric experiments and immunoblotting. The potential synthetic lethal relationship between candidates genes identified in the screen and oncogenic CTNNB1 was also investigated in a different cellular context, a colorectal HCT116 isogenic cell line pair.
RESULTS: We first determined the experimental conditions that led to the efficient expression of shRNA against CTNNB1 and maximal reduction of β-catenin signaling activity in response to doxycycline treatment. Following high throughput screening in which 687 genes coding for kinases and proteins related to kinases (such as pseudokinases and phosphatases) were targeted, we identified 52 genes required for HuH6 survival. The silencing of five of these genes selectively impaired the viability of HuH6 cells with high β-catenin signaling: HGS, STRADA, FES, BRAF and PKMYT1. Among these candidates, HGS depletion had the strongest inhibitory effect on cell growth and led to apoptosis specifically in HuH6 with high β-catenin activity, while HuH6 with low β-catenin activity were spared. In addition, HGS was identified as a potential synthetic lethal partner of oncogenic CTNNB1 in the HCT116 colorectal isogenic cell line pair.
CONCLUSIONS: These results demonstrate the existence of crosstalk between β-catenin signaling and HGS. Importantly, HGS depletion specifically affected cells with uncontrolled β-catenin signaling activity in two different types of cancer (Hepatoblastoma HuH6 and colorectal HCT116), and thus may represent a new potential target for novel therapeutic strategies in liver and colorectal cancer.
Ruiz Esparza-Garrido R, Torres-Márquez ME, Viedma-Rodríguez R, et al.Breast cancer cell line MDA-MB-231 miRNA profile expression after BIK interference: BIK involvement in autophagy.
Tumour Biol. 2016; 37(5):6749-59 [PubMed
] Related Publications
B-cell lymphoma 2 (BCL2)-interacting killer (apoptosis inducing) (BIK) has been proposed as a tumor suppressor in diverse types of cancers. However, BIK's overexpression in breast cancer (BC) and in non-small lung cancer cells (NSCLCs), associated with a poor prognosis, suggests its participation in tumor progression. In this study, we evaluated the global expression pattern of microRNAs (miRNAs), messenger RNA (mRNA) expression changes in autophagy, and autophagic flux after BIK interference. BIK gene expression was silenced by small interfering RNA (siRNA) in BC cell MDA-MB-231, and BIK interference efficiency was tested by real-time PCR and by Western blotting. BIK expression levels decreased by 75 ± 18 % in the presence of 600 nM siRNA, resulting in the abolishment of BIK expression by 94 ± 30 %. BIK interference resulted in the overexpression of 17 miRNAs that, according to the DIANA-miRPath v3.0 database, are mainly implied in the control of cell signaling, gene expression, and autophagy. The autophagy array revealed downregulation of transcripts which participate in autophagy, and their interactome revealed a complex network, where hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), α-synuclein (SNCA), unc-51-like autophagy activating kinase 1/2 (ULK1/2), and mitogen-activated protein kinase 3 (MAPK3) were shown to be signaling hubs. LC3-II expression-an autophagy marker-was increased by 169 ± 25 % after BIK interference, which indicates the involvement of BIK in autophagy. Altogether, our results indicate-for the first time-that BIK controls the expression of miRNAs, as well as the autophagic flux in MDA-MB-231 cells.
Here, we developed an isogenic cell model of "stemness" to facilitate protein biomarker discovery in breast cancer. For this purpose, we used knowledge gained previously from the study of the mouse mammary tumor virus (MMTV). MMTV initiates mammary tumorigenesis in mice by promoter insertion adjacent to two main integration sites, namely Int-1 (Wnt1) and Int-2 (Fgf3), which ultimately activates Wnt/β-catenin signaling, driving the propagation of mammary cancer stem cells (CSCs). Thus, to develop a humanized model of MMTV signaling, we over-expressed WNT1 and FGF3 in MCF7 cells, an ER(+) human breast cancer cell line. We then validated that MCF7 cells over-expressing both WNT1 and FGF3 show a 3.5-fold increase in mammosphere formation, and that conditioned media from these cells is also sufficient to promote stem cell activity in untransfected parental MCF7 and T47D cells, as WNT1 and FGF3 are secreted factors. Proteomic analysis of this model system revealed the induction of i) EMT markers, ii) mitochondrial proteins, iii) glycolytic enzymes and iv) protein synthesis machinery, consistent with an anabolic CSC phenotype. MitoTracker staining validated the expected WNT1/FGF3-induced increase in mitochondrial mass and activity, which presumably reflects increased mitochondrial biogenesis. Importantly, many of the proteins that were up-regulated by WNT/FGF-signaling in MCF7 cells, were also transcriptionally over-expressed in human breast cancer cells in vivo, based on the bioinformatic analysis of public gene expression datasets of laser-captured patient samples. As such, this isogenic cell model should accelerate the discovery of new biomarkers to predict clinical outcome in breast cancer, facilitating the development of personalized medicine.Finally, we used mitochondrial mass as a surrogate marker for increased mitochondrial biogenesis in untransfected MCF7 cells. As predicted, metabolic fractionation of parental MCF7 cells, via MitoTracker staining, indicated that high mitochondrial mass is a new metabolic biomarker for the enrichment of anabolic CSCs, as functionally assessed by mammosphere-forming activity. This observation has broad implications for understanding the role of mitochondrial biogenesis in the propagation of stem-like cancer cells. Technically, this general metabolic approach could be applied to any cancer type, to identify and target the mitochondrial-rich CSC population.The implications of our work for understanding the role of mitochondrial metabolism in viral oncogenesis driven by random promoter insertions are also discussed, in the context of MMTV and ALV infections.
Etiology of human breast cancer is unknown, whereas the Mouse Mammary Tumor Virus (MMTV) is recognized as the etiologic agent of mouse mammary carcinoma. Moreover, this experimental model contributed substantially to our understanding of many biological aspects of the human disease. Several data strongly suggest a causative role of MMTV in humans, such as the presence of viral sequences in a high percentage of infiltrating breast carcinoma and in its preinvasive lesions, the production of viral particles in primary cultures of breast cancer, the ability of the virus to infect cells in culture. This paper demonstrates that MMTV is present in human saliva and salivary glands. MMTV presence was investigated by fluorescent PCR, RT-PCR, FISH, immunohistochemistry, and whole transcriptome analysis. Saliva was obtained from newborns, children, adults, and breast cancer patients. The saliva of newborns is MMTV-free, whereas MMTV is present in saliva of children (26.66%), healthy adults (10.60%), and breast cancer patients (57.14% as DNA and 33.9% as RNA). MMTV is also present in 8.10% of salivary glands. RNA-seq analysis performed on saliva of a breast cancer patient demonstrates a high expression of MMTV RNA in comparison to negative controls. The possibility of a contamination by murine DNA was excluded by murine mtDNA and IAP LTR PCR. These findings confirm the presence of MMTV in humans, strongly suggest saliva as route in inter-human infection, and support the hypothesis of a viral origin for human breast carcinoma.
MicroRNAs and siRNAs belong to a family of small noncoding RNAs which bind through partial sequence complementarity to 3'-UTR regions of mRNA from target genes, resulting in the regulation of gene expression. MicroRNAs have become an attractive target for genetic and pharmacological modulation due to the critical function of their target proteins in several signaling pathways, and their expression profiles have been found to be altered in various cancers. A promising technology platform for selective silencing of cell and/or viral gene expression using siRNAs is currently in development. Cervical cancer is the most common cancer in women in the developing world and sexually transmitted infection with HPV is the cause of this malignancy. Therefore, a cascade of abnormal events is induced during cervical carcinogenesis, including the induction of genomic instability, reprogramming of cellular metabolic pathways, deregulation of cell proliferation, inhibition of apoptotic mechanisms, disruption of cell cycle control mechanisms, and alteration of gene expression. Thus, in the present review article, we highlight new research on microRNA expression profiles which may be utilized as biomarkers for cervical cancer. Furthermore, we discuss selective silencing of HPV E6 and E7 with siRNAs which represents a potential gene therapy strategy against cervical cancer.
Oneyama C, Yoshikawa Y, Ninomiya Y, et al.Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression.
Oncogene. 2016; 35(4):501-12 [PubMed
] Related Publications
c-Src is upregulated in various human cancers, suggesting its role in malignant progression. However, the molecular circuits of c-Src oncogenic signaling remain elusive. Here we show that Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression. Previously, we showed that transformation of fibroblasts is promoted by the relocation of c-Src to non-raft membranes. In this study, we identified Fer and ezrin as non-raft c-Src targets. c-Src directly activated Fer by initiating its autophosphorylation, which was further amplified by Fer oligomerization. Fer interacted with active c-Src at focal adhesion membranes and activated Fer-phosphorylated ezrin to induce cell transformation. Fer was also crucial for cell transformation induced by v-Src or epidermal growth-factor receptor activation. Furthermore, Fer activation was required for tumorigenesis and invasiveness in some cancer cells in which c-Src is upregulated. We propose that the Src-Fer axis represents a new therapeutic target for treatment of a subset of human cancers.
Viedma-Rodríguez R, Ruiz Esparza-Garrido R, Baiza-Gutman LA, et al.Involvement of multiple cellular pathways in regulating resistance to tamoxifen in BIK-suppressed MCF-7 cells.
Tumour Biol. 2015; 36(9):6991-7005 [PubMed
] Related Publications
Majority of women with estrogen receptor (ER)-positive breast cancers initially respond to hormone therapies such as tamoxifen (TAM; antagonist of estrogen). However, many tumors eventually become resistant to TAM. Therefore, understanding the various cellular components involved in causing resistance to TAM is of paramount importance in designing novel entities for efficacious hormone therapy. Previously, we found that suppression of BIK gene expression induced TAM resistance in MCF-7 breast cancer cells. In order to understand the response of these cells to TAM and its association with resistance, a microarray analysis of gene expression was performed in the BIK-suppressed MCF-7 cells and compared it to the TAM-only-treated cells (controls). Several genes participating in various cellular pathways were identified. Molecules identified in the drug resistance pathway were 14-3-3z or YWHAZ, WEE1, PRKACA, NADK, and HSP90AA 1. Further, genes involved in cell cycle control, apoptosis, and cell proliferation were also found differentially expressed in these cells. Transcriptional and translational analysis of key molecules such as STAT2, AKT 3, and 14-3-3z revealed similar changes at the messenger RNA (mRNA) as well as at the protein level. Importantly, there was no cytotoxic effect of TAM on BIK-suppressed MCF-7 cells. Further, these cells were not arrested at the G0-G1 phase of the cell cycle although 30 % of BIK-suppressed cells were arrested at the G2 phase of the cycle on TAM treatment. Furthermore, we found a relevant interaction between 14-3-3z and WEE1, suggesting that the cytotoxic effect of TAM was prevented in BIK-suppressed cells because this interaction leads to transitory arrest in the G2 phase leading to the repair of damaged DNA and allowing the cells to proliferate.
Nag K, Pal NRA Multiobjective Genetic Programming-Based Ensemble for Simultaneous Feature Selection and Classification.
IEEE Trans Cybern. 2016; 46(2):499-510 [PubMed
] Related Publications
We present an integrated algorithm for simultaneous feature selection (FS) and designing of diverse classifiers using a steady state multiobjective genetic programming (GP), which minimizes three objectives: 1) false positives (FPs); 2) false negatives (FNs); and 3) the number of leaf nodes in the tree. Our method divides a c -class problem into c binary classification problems. It evolves c sets of genetic programs to create c ensembles. During mutation operation, our method exploits the fitness as well as unfitness of features, which dynamically change with generations with a view to using a set of highly relevant features with low redundancy. The classifiers of i th class determine the net belongingness of an unknown data point to the i th class using a weighted voting scheme, which makes use of the FP and FN mistakes made on the training data. We test our method on eight microarray and 11 text data sets with diverse number of classes (from 2 to 44), large number of features (from 2000 to 49 151), and high feature-to-sample ratio (from 1.03 to 273.1). We compare our method with a bi-objective GP scheme that does not use any FS and rule size reduction strategy. It depicts the effectiveness of the proposed FS and rule size reduction schemes. Furthermore, we compare our method with four classification methods in conjunction with six features selection algorithms and full feature set. Our scheme performs the best for 380 out of 474 combinations of data sets, algorithm and FS method.
Nizard P, Ezan F, Bonnier D, et al.Integrative analysis of high-throughput RNAi screen data identifies the FER and CRKL tyrosine kinases as new regulators of the mitogenic ERK-dependent pathways in transformed cells.
BMC Genomics. 2014; 15:1169 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Cell proliferation is a hallmark of cancer and depends on complex signaling networks that are chiefly supported by protein kinase activities. Therapeutic strategies have been used to target specific kinases but new methods are required to identify combined targets and improve treatment. Here, we propose a small interfering RNA genetic screen and an integrative approach to identify kinase networks involved in the proliferation of cancer cells.
RESULTS: The functional siRNA screen of 714 kinases in HeLa cells identified 91 kinases implicated in the regulation of cell growth, most of them never being reported in previous whole-genome siRNA screens. Based on gene ontology annotations, we have further discriminated between two classes of kinases that, when suppressed, result in alterations of the mitotic index and provoke cell-cycle arrest. Extinguished kinases that lead to a low mitotic index mostly include kinases implicated in cytosolic signaling. In contrast, extinguished kinases that result in a high mitotic index mostly include kinases implicated in cell division. By mapping hit kinases in the PhosphPOINT phosphoprotein database, we generated scale-free networks consisting of 449 and 661 protein-protein interactions for kinases from low MI and high MI groups, respectively. Further analyses of the kinase interactomes revealed specific modules such as FER- and CRKL-containing modules that connect three members of the epidermal growth factor receptor (EGFR) family, suggesting a tight control of the mitogenic EGF-dependent pathway. Based on experimental studies, we confirm the involvement of these two kinases in the regulation of tumor cell growth.
CONCLUSION: Based on a combined approach of large kinome-wide siRNA screens and ontology annotations, our study identifies for the first time two kinase groups differentially implicated in the control of cell proliferation. We further demonstrate that integrative analysis of the kinase interactome provides key information which can be used to facilitate or optimize target design for new therapeutic strategies. The complete list of protein-protein interactions from the two functional kinase groups will provide a useful database for future investigations.
van Kruchten M, de Vries EF, Arts HJ, et al.Assessment of estrogen receptor expression in epithelial ovarian cancer patients using 16α-18F-fluoro-17β-estradiol PET/CT.
J Nucl Med. 2015; 56(1):50-5 [PubMed
] Related Publications
UNLABELLED: The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of (18)F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients.
METHODS: (18)F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor (18)F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. (18)F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis.
RESULTS: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor (18)F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative (18)F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70-1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. (18)F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that (18)F-FES PET could provide reliable information about current tumor ERα status.
CONCLUSION: (18)F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of (18)F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.
Ávila-Moreno F, Armas-López L, Álvarez-Moran AM, et al.Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis.
PLoS One. 2014; 9(12):e114104 [PubMed
] Free Access to Full Article Related Publications
Lung cancer is the leading cause of death from malignant diseases worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases. NSCLC is characterized by frequent genomic imbalances and copy number variations (CNVs), but the epigenetic aberrations that are associated with clinical prognosis and therapeutic failure remain not completely identify. In the present study, a total of 55 lung cancer patients were included and we conducted genomic and genetic expression analyses, immunohistochemical protein detection, DNA methylation and chromatin immunoprecipitation assays to obtain genetic and epigenetic profiles associated to prognosis and chemoresponse of NSCLC patients. Finally, siRNA transfection-mediated genetic silencing and cisplatinum cellular cytotoxicity assays in NSCLC cell lines A-427 and INER-37 were assessed to describe chemoresistance mechanisms involved. Our results identified high frequencies of CNVs (66-51% of cases) in the 7p22.3-p21.1 and 7p15.3-p15.2 cytogenetic regions. However, overexpression of genes, such as MEOX2, HDAC9, TWIST1 and AhR, at 7p21.2-p21.1 locus occurred despite the absence of CNVs and little changes in DNA methylation. In contrast, the promoter sequences of MEOX2 and TWIST1 displayed significantly lower/decrease in the repressive histone mark H3K27me3 and increased in the active histone mark H3K4me3 levels. Finally these results correlate with poor survival in NSCLC patients and cellular chemoresistance to oncologic drugs in NSCLC cell lines in a MEOX2 and TWIST1 overexpression dependent-manner. In conclusion, we report for the first time that MEOX2 participates in chemoresistance irrespective of high CNV, but it is significantly dependent upon H3K27me3 enrichment probably associated with aggressiveness and chemotherapy failure in NSCLC patients, however additional clinical studies must be performed to confirm our findings as new probable clinical markers in NSCLC patients.
BACKGROUND: Malignant gliomas are complex systems containing a number of factors that drive tumor initiation and progression, including genetic aberrations that lead to extensive cellular heterogeneity within the neoplastic compartment. Mouse models recapitulate these genetic aberrations, but readily observable heterogeneity remains challenging.
METHODS: To interrogate cellular heterogeneity in mouse glioma models, we utilized a replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor/tumor virus A (RCAS-tva) system to generate spontaneous mouse gliomas that contained a Sox2-enhanced green fluorescent protein (EGFP) reporter. Glial fibrillary acidic protein-tva mice were crossed with Sox2-EGFP mice, and tumors were initiated that contained a subpopulation of Sox2-EGFP-high cells enriched for tumor-initiating cell properties such as self-renewal, multilineage differentiation potential, and perivascular localization.
RESULTS: Following implantation into recipient mice, Sox2-EGFP-high cells generated tumors containing Sox2-EGFP-high and Sox2-EGFP-low cells. Kinomic analysis of Sox2-EGFP-high cells revealed activation of known glioma signaling pathways that are strongly correlated with patient survival including platelet-derived growth factor receptor beta, phosphoinositide-3 kinase, and vascular endothelial growth factor. Our functional analysis identified active feline sarcoma (Fes) signaling in Sox2-EGFP-high cells. Fes negatively correlated with glioma patient survival and was coexpressed with Sox2-positive cells in glioma xenografts and primary patient-derived tissue.
CONCLUSIONS: Our RCAS-tva/Sox2-EGFP model will empower closer examination of cellular heterogeneity and will be useful for identifying novel glioma pathways as well as testing preclinical treatment efficacy.
MLL1, located on human chromosome 11, is disrupted in distinct recurrent chromosomal translocations in several leukemia subsets. Studying the MLL1 gene and its oncogenic variants has provided a paradigm for understanding cancer initiation and maintenance through aberrant epigenetic gene regulation. Here we review the historical development of model systems to recapitulate oncogenic MLL1-rearrangement (MLL-r) alleles encoding mixed-lineage leukemia fusion proteins (MLL-FPs) or internal gene rearrangement products. These largely mouse and human cell/xenograft systems have been generated and used to understand how MLL-r alleles affect diverse pathways to result in a highly penetrant, drug-resistant leukemia. The particular features of the animal models influenced the conclusions of mechanisms of transformation. We discuss significant downstream enablers, inhibitors, effectors, and collaborators of MLL-r leukemia, including molecules that directly interact with MLL-FPs and endogenous mixed-lineage leukemia protein, direct target genes of MLL-FPs, and other pathways that have proven to be influential in supporting or suppressing the leukemogenic activity of MLL-FPs. The use of animal models has been complemented with patient sample, genome-wide analyses to delineate the important genomic and epigenomic changes that occur in distinct subsets of MLL-r leukemia. Collectively, these studies have resulted in rapid progress toward developing new strategies for targeting MLL-r leukemia and general cell-biological principles that may broadly inform targeting aberrant epigenetic regulators in other cancers.
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.
METHODS: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients.
RESULTS: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17.
CONCLUSIONS: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.
Viedma-Rodríguez R, Baiza-Gutman L, Salamanca-Gómez F, et al.Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review).
Oncol Rep. 2014; 32(1):3-15 [PubMed
] Related Publications
Anti-estrogens such as tamoxifen are widely used in the clinic to treat estrogen receptor-positive breast tumors. Patients with estrogen receptor-positive breast cancer initially respond to treatment with anti-hormonal agents such as tamoxifen, but remissions are often followed by the acquisition of resistance and, ultimately, disease relapse. The development of a rationale for the effective treatment of tamoxifen-resistant breast cancer requires an understanding of the complex signal transduction mechanisms. In the present study, we explored some mechanisms associated with resistance to tamoxifen, such as pharmacologic mechanisms, loss or modification in estrogen receptor expression, alterations in co-regulatory proteins and the regulation of the different signaling pathways that participate in different cellular processes such as survival, proliferation, stress, cell cycle, inhibition of apoptosis regulated by the Bcl-2 family, autophagy, altered expression of microRNA, and signaling pathways that regulate the epithelial-mesenchymal transition in the tumor microenvironment. Delineation of the molecular mechanisms underlying the development of resistance may aid in the development of treatment strategies to enhance response and compromise resistance.
Development of head and neck squamous cell carcinoma (HNSCC) is characterized by accumulation of mutations in several oncogenes and tumor suppressor genes. We have formerly described the mutation pattern of HNSCC and described NOTCH signaling pathway alterations. Given the complexity of the HNSCC, here we extend the previous study to understand the overall HNSCC mutation context and to discover additional genetic alterations. We performed high depth targeted exon sequencing of 51 highly actionable cancer-related genes with a high frequency of mutation across many cancer types, including head and neck. DNA from primary tumor tissues and matched normal tissues was analyzed for 37 HNSCC patients. We identified 26 non-synonymous or stop-gained mutations targeting 11 of 51 selected genes. These genes were mutated in 17 out of 37 (46%) studied HNSCC patients. Smokers harbored 3.2-fold more mutations than non-smokers. Importantly, TP53 was mutated in 30%, NOTCH1 in 8% and FGFR3 in 5% of HNSCC. HPV negative patients harbored 4-fold more TP53 mutations than HPV positive patients. These data confirm prior reports of the HNSCC mutational profile. Additionally, we detected mutations in two new genes, CEBPA and FES, which have not been previously reported in HNSCC. These data extend the spectrum of HNSCC mutations and define novel mutation targets in HNSCC carcinogenesis, especially for smokers and HNSCC without HPV infection.
Yang Y, Xiang K, Yang YX, et al.An individually coated near-infrared fluorescent protein as a safe and robust nanoprobe for in vivo imaging.
Nanoscale. 2013; 5(21):10345-52 [PubMed
] Related Publications
A prerequisite for in vivo fluorescence imaging is the safety of fluorescent probes. Among all fluorescent probes, fluorescent proteins (FPs) might be the safest ones, which have been widely used in biological sciences at the gene level. But FPs have not been used in vivo in the purified form yet due to the instability of proteins. Here, we individually coat near-infrared (NIR) FPs (NIRFPs) with a silica nanoshell, resulting in NIRFP@silica, one of the safest and brightest NIR fluorescent nanoprobes with a quantum yield of 0.33 for in vivo imaging. The silica shell not only protects NIRFPs from denaturation and metabolic digestion, but also enhances the quantum yield and photostability of the coated NIRFPs. When injected via the tail vein, NIRFP@silica NPs can distribute all over the mouse body, and then can be efficiently eliminated through urine in 24 h, demonstrating its potential applications as a safe and robust NIR fluorescence probe for whole body imaging.
UNLABELLED: The presence of estrogen receptor (ER) in breast cancer is a prognostic indicator for both disease-free and overall survival. 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) with PET is a noninvasive test for evaluation of ER expression and has been used for predicting response to endocrine therapy in patients with ER-positive metastatic breast cancer. The purpose of this study was to correlate (18)F-FES PET and ER expression in patients with primary, operable breast cancer.
METHODS: Forty-eight patients were prospectively enrolled in an institutional review board-approved protocol and signed an informed consent form. All patients had undergone (18)F-FES PET preoperatively. Clinical characteristics, tumor characteristics, and treatment outcomes were recorded. Immunohistochemical analysis for ER and progesterone receptor (PgR) percentage expression (46 surgical, 2 core biopsy specimens) was performed. (18)F-FES PET standardized uptake value (SUV) of the breast lesion was correlated with percentage immunohistochemistry ER and PgR expression. (18)F-FES PET SUV was quantified, with a value of 1.5 or more considered positive, and ER and PgR was quantified, with 1% or more considered positive. Formalin-fixed paraffin-embedded tissue was available for 44 patients (42 surgical, 2 core biopsy specimens). We used a microarray platform, and estrogen-related gene expression data (ESR1, ESR2, and PGR) were compared with (18)F-FES PET SUV (Spearman rank correlation). Tumor size, ductal histology, grade, HER2-neu overexpression, PgR expression, estradiol level, body mass index (BMI), and lean BMI were compared with (18)F-FES PET uptake using univariate and multivariate analysis.
RESULTS: Forty-eight patients completed our protocol, and 2 patients did not undergo surgery because bone metastases were identified preoperatively on (18)F-FES PET. Eighty-three percent of our patients were stage I or II, with a median tumor size of 1.9 cm. Forty-one patients underwent a sentinel node biopsy. Twenty-one patients had nodal involvement. (18)F-FES PET identified 5 patients with axillary nodal uptake (median SUV, 3.0; range, 1.7-6.9). These 5 patients had ER-positive breast cancer, and all had more than 4 positive nodes at the time of axillary node dissection. (18)F-FES PET SUV was associated with immunohistochemistry ER expression. The sensitivity and specificity of the (18)F-FES PET for the breast lesion were 0.85 and 0.75, respectively. Estrogen and progesterone gene expression (ESR1, ESR2, and PGR) was not associated with (18)F-FES PET SUV (Spearman rank correlation). We found a significant correlation between (18)F-FES PET SUV and tumor size (P = 0.0015) but not with ductal histology, grade, HER2-neu overexpression, PgR, estradiol, BMI, or lean BMI (logistic regression). ER expression (P < 0.001) and tumor size (P < 0.0001) were significant on multivariate regression analysis.
CONCLUSION: (18)F-FES PET SUV correlated with ER immunohistochemistry expression but not gene expression in our patients with early breast cancer. We found that size of primary tumor was significantly associated with (18)F-FES PET SUV. (18)F-FES PET is highly predictive for metastatic disease and helped in the identification of patients with metastatic disease in a preoperative setting.
Kawakami M, Ishikawa R, Amano Y, et al.Detection of novel paraja ring finger 2-fer tyrosine kinase mRNA chimeras is associated with poor postoperative prognosis in non-small cell lung cancer.
Cancer Sci. 2013; 104(11):1447-54 [PubMed
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Previously, we reported that the overexpression of fer tyrosine kinase (FER), a non-receptor tyrosine kinase, is correlated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer (NSCLC). In the present study, we further analyzed FER-overexpressed NSCLC cases and identified various patterns of chimeric mRNAs, composed of paraja ring finger 2 (PJA2) and FER. We detected no genomic rearrangements between PJA2 and FER and attributed these chimeric mRNAs to alterations at the transcriptome level: i.e., trans-splicing. Several chimeric patterns were detected concurrently in each patient, and the pattern sets varied among patients, although the pattern in which PJA2 exon 1 was fused to FER exon 3 (designated as Pe1-Fe3 mRNA) was detected constantly. Therefore, in a wide screening for PJA2-FER mRNAs in NSCLC, we focused on this chimeric pattern as a representative chimera. In analyses of 167 NSCLC samples, Pe1-Fe3 mRNA was identified in about 10% of the patients, and the presence of chimeric mRNA was significantly correlated with a high expression level of parental FER mRNA. Furthermore, we found that the detection of Pe1-Fe3 mRNA was correlated with poor postoperative survival periods in NSCLC, consistent with a previous finding in which FER overexpression was correlated with poor postoperative prognosis in NSCLC. This report is the first to suggest a correlation between chimeric mRNA and the expression level of parental mRNA. Furthermore, our findings may be clinically beneficial, suggesting that PJA2-FER mRNAs might serve as a novel prognostic biomarker in NSCLC.
Rocha J, Zouanat FZ, Zoubeidi A, et al.The Fer tyrosine kinase acts as a downstream interleukin-6 effector of androgen receptor activation in prostate cancer.
Mol Cell Endocrinol. 2013; 381(1-2):140-9 [PubMed
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Castrate-resistant prostate cancer (CRPC) is invariably lethal and still poorly understood. IL-6/pSTAT3 appears critical as elevated IL-6 and pSTAT3 correlate with CRPC and poor prognosis. We previously reported on the Fer tyrosine kinase being an integral component of the IL-6 pathway in PC by controlling STAT3. Since IL-6 also controls androgen receptor (AR) signaling via pSTAT3, we tested if Fer participates in this cross-talk. We report for the first time that in addition to STAT3, Fer is required for IL-6 mediated AR activation by phosphorylating AR tyrosine 223 and binding via its SH2 domain. Fer controls IL-6 induced growth response and PSA expression, while modestly contributing to EGF and IGF-1 effects. Finally, Fer, AR and pSTAT3 co-localize in the PC cell nucleus, including in prostate tissues from CRPC patients. Altogether these findings support a Fer contribution to aberrant AR signaling via pSTAT3 cross-talks during CRPC progression.
Lennartsson J, Ma H, Wardega P, et al.The Fer tyrosine kinase is important for platelet-derived growth factor-BB-induced signal transducer and activator of transcription 3 (STAT3) protein phosphorylation, colony formation in soft agar, and tumor growth in vivo.
J Biol Chem. 2013; 288(22):15736-44 [PubMed
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Fer is a cytoplasmic tyrosine kinase that is activated in response to platelet-derived growth factor (PDGF) stimulation. In the present report, we show that Fer associates with the activated PDGF β-receptor (PDGFRβ) through multiple autophosphorylation sites, i.e. Tyr-579, Tyr-581, Tyr-740, and Tyr-1021. Using low molecular weight inhibitors, we found that PDGF-BB-induced Fer activation is dependent on PDGFRβ kinase activity, but not on the enzymatic activity of Src or Jak kinases. In cells in which Fer was down-regulated using siRNA, PDGF-BB was unable to induce phosphorylation of STAT3, whereas phosphorylations of STAT5, ERK1/2, and Akt were unaffected. PDGF-BB-induced activation of STAT3 occurred also in cells expressing kinase-dead Fer, suggesting a kinase-independent adaptor role of Fer. Expression of Fer was dispensable for PDGF-BB-induced proliferation and migration but essential for colony formation in soft agar. Tumor growth in vivo was delayed in cells depleted of Fer expression. Our data suggest a critical role of Fer in PDGF-BB-induced STAT3 activation and cell transformation.
BACKGROUND: Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative.
OBJECTIVES: The objective of this study was to identify susceptibility genes for PTC.
METHODS: A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies.
RESULTS: Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants.
CONCLUSIONS: Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.
Zhao Z, Yoshida Y, Kurokawa T, et al.18F-FES and 18F-FDG PET for differential diagnosis and quantitative evaluation of mesenchymal uterine tumors: correlation with immunohistochemical analysis.
J Nucl Med. 2013; 54(4):499-506 [PubMed
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UNLABELLED: The aim of this study was to investigate the relationship between the tumor uptake of 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) and (18)F-FDG using PET and expressions of sex hormone receptors, such as estrogen receptor (ER), as well as glucose transporter 1 (GLUT-1) and Ki-67 analyzed by the immunohistochemistry method in mesenchymal uterine tumors.
METHODS: Forty-seven patients with mesenchymal uterine tumors were studied with (18)F-FES and (18)F-FDG PET. Postoperative pathologic diagnosis revealed 33 uterine leiomyomas and 14 uterine sarcomas. Tissue samples were assayed for expression of ERα, ERβ, progesterone receptor (PR), PR-B, GLUT-1, and Ki-67 by an immunohistochemistry method. Standardized uptake values (SUVs) for (18)F-FES and (18)F-FDG were compared with the semiquantitative immunoreactive score (0-12) and quantitative labeling index (LI) for Ki-67 in immunohistochemistry.
RESULTS: (18)F-FES uptake was significantly lower (P < 0.001) and the (18)F-FDG uptake and SUV ratio of (18)F-FDG to (18)F-FES ((18)F-FDG/(18)F-FES ratio) (P < 0.005 and P < 0.001, respectively) were significantly higher in uterine sarcomas than in leiomyomas. Immunohistochemistry analysis showed significantly higher expressions of ERα, PR, and PR-B in uterine leiomyomas than in sarcomas. The Ki-67 LI was significantly greater in uterine sarcomas than in leiomyomas. Correlation analysis for all tumors showed positive correlations between (18)F-FES SUV and immunohistochemistry scores of ERα, PR (P < 0.001), and PR-B (P < 0.005) as well as between (18)F-FDG SUV and GLUT-1 and Ki-67 (P < 0.001). However, the (18)F-FDG/(18)F-FES ratio showed significantly negative correlations with ERα, PR (P < 0.001), and PR-B (P < 0.005) and a positive correlation with Ki-67 LI (P < 0.001). In uterine sarcomas, ERα and (18)F-FES SUV showed a positive correlation (P < 0.001) in a low SUV range, and the (18)F-FDG/(18)F-FES ratio showed positive correlations with ERβ and GLUT-1 expression (P < 0.005).
CONCLUSION: (18)F-FES and (18)F-FDG PET showed correlations between tracer uptake and expressions of sex hormone receptors, GLUT-1, and Ki-67 in mesenchymal uterine tumors. The (18)F-FDG/(18)F-FES ratio was correlated with Ki-67, GLUT-1, and ERβ in uterine sarcoma. Functional PET imaging and PET parameters would be useful noninvasive biomarkers for the assessment of tumor hormone receptor expression, glucose metabolism, and proliferation and for differential diagnosis of uterine leiomyoma and sarcoma.
Huang H, Xiang Y, Su B, et al.Potential roles for Gfi1 in the pathogenesis and proliferation of glioma.
Med Hypotheses. 2013; 80(5):629-32 [PubMed
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Glioblastoma multiforme (GBM) is a major form of adult brain tumour with relatively poor prognosis and high mortality. Temozolomide (TMZ)-based chemotherapy following neurosurgery and radiotherapy has been suggested as the first line of treatment and is proven to effectively prolong overall survival and enhance patient quality of life. However, not all patients benefit from this treatment because of drug resistance. Even patients with TMZ-sensitive GBM may become resistant, which is partly due to the restoration of activity of the DNA repair enzyme O(6)-methylguanine-DNA-methyltransferase (MGMT); thus, patients cannot evade eventual tumour recurrence. The cellular activity of MGMT is the most important determinant of TMZ-resistance. However, some patients with a low level of activated MGMT are also TMZ-resistant. The aberrant expression of HOXA9, one of the 39 class I homeobox genes, is a marker of poor prognosis, and its level gradually increases with histologic malignant progression, shorter time to overall survival (OS) and free progression survival (FPS) in glioma patients, which further supports an oncogenic role for HOXA9 in gliomas. The HOXA9-PI3K signalling pathway is an important mechanism in GBM that is independent of MGMT promoter methylation status. The DNA binding sites of growth factor independent-1 (Gfi1) can overlap with the HOXA9 promoter through the "AATC" versus "GATT" core sequence. The competition for this binding site inhibits the expression of HOXA9 and induces different transcriptional outcomes, which suggests a new direction for investigation of the mechanism underlying targeted therapy of malignant gliomas.
Miyata Y, Kanda S, Sakai H, Greer PAFeline sarcoma-related protein expression correlates with malignant aggressiveness and poor prognosis in renal cell carcinoma.
Cancer Sci. 2013; 104(6):681-6 [PubMed
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Feline sarcoma-related protein (Fer) is a ubiquitously expressed non-receptor protein tyrosine kinase associated with proliferation in various cancer cells. However, no reports have described the pathological roles and prognostic value of Fer expression in renal cell carcinoma (RCC). We investigated Fer expression in three RCC cell lines (ACHN, Caki-1, and Caki-2) and in normal tubule cells (HK-2) by immunoblotting. Fer expression was highest in ACHN cells, with Caki-1 showing intermediate levels and Caki-2 showing low levels, and was undetectable in HK-2. RNA interference was therefore used to assess the effects of Fer knockdown in ACHN. Knockdown of Fer expression was found to inhibit RCC cell proliferation and colony formation. Immunohistochemical analysis of 131 human RCC tissues (110 conventional, 11 chromophobe, and 10 papillary) investigated relationships between Fer expression and clinicopathological features, including cancer cell proliferation, apoptosis, and prognostic value for survival. In human tissues, Fer expression was significantly higher in cancer cells than in normal tubules. In addition, expression levels correlated with cancer cell proliferation, but not with apoptosis. Multivariate analysis indicated associations of Fer expression with pT stage, tumor grade, and metastasis (P < 0.001). Fer expression was also prognostic for cause-specific survival according to multivariate analysis (hazard ratio, 3.89; 95% confidence interval, 1.02-14.84, P = 0.047). Fer expression correlates with RCC cell proliferation both in vitro and in vivo, and with tumor progression and survival. This represents useful information for discussing the pathological and clinical significance of Fer in RCC.
The products of the oncogene Fes and JAK3 are tyrosine kinases, whose expressions are elevated in tumor growth, angiogenesis, and metastasis. Phosphatidic acid, as synthesized by phospholipase D (PLD), enhances cancer cell survival. We report a new signaling pathway that integrates the two kinases with the lipase. A new JAK3-Fes-PLD2 axis is responsible for the highly proliferative phenotype of MDA-MB-231 breast cancer cells. Conversely, this pathway is maintained at a low rate of expression and activity levels in untransformed cells such as MCF10A. We also deciphered the inter-regulation that exists between the two kinases (JAK3 and the oncogene Fes) and between these two kinases and the lipase (PLD2). Whereas JAK3 and Fes marginally activate PLD2 in non-transformed cells, these kinases greatly enhance (>200%) PLD activity following protein-protein interaction through the SH2 domain and the Tyr-415 residue of PLD2. We also found that phosphatidic acid enhances Fes activity in MDA-MB-231 cells providing a positive activation loop between Fes and PLD2. In summary, the JAK3, Fes and PLD2 interactions in transformed cells maintain PLD2 at an enhanced level that leads to abnormal cell growth. Modulating this new JAK3-Fes-PLD2 pathway could be important to control the highly invasive phenotype of breast cancer cells.
The c-abl proto-oncogene encodes a unique protein-tyrosine kinase (Abl) distinct from c-Src, c-Fes, and other cytoplasmic tyrosine kinases. In normal cells, Abl plays prominent roles in cellular responses to genotoxic stress as well as in the regulation of the actin cytoskeleton. Abl is also well known in the context of Bcr-Abl, the oncogenic fusion protein characteristic of chronic myelogenous leukemia. Selective inhibitors of Bcr-Abl, of which imatinib is the prototype, have had a tremendous impact on clinical outcomes in chronic myelogenous leukemia and revolutionized the field of targeted cancer therapy. In this minireview, we focus on the structural organization and dynamics of Abl kinases and how these features influence inhibitor sensitivity.
A continuous monitoring of the whole tumor burden of individuals in orthotopic tumor models is a desirable aim and requires non-invasive imaging methods. Here we investigated whether quantification of a xenograft tumor intrinsic fluorescence signal can be used to evaluate tumor growth and response to chemotherapy. Stably fluorescence protein (FP) expressing cell clones of colorectal carcinoma and germ cell tumor lines were generated by lentiviral transduction using the FPs eGFP, dsRed2, TurboFP635, and mPlum. Applying subcutaneous tumor models in different experimental designs, specific correlations between measured total fluorescence intensity (FI) and the tumor volume (V) could be established. The accuracy of correlation of FI and V varied depending on the cell model used. The application of deep-red FP expressing xenografts (TurboFP635, mPlum) was observed to result in improved correlations. This was also reflected by the results of a performed error analysis. In a model of visceral growing mPlum tumors, measurements of FI could be used to follow growth and response to chemotherapy. However, in some cases final necropsy revealed the existence of additional, deeper located tumors that had not been detected in vivo by their mPlum signal. Consistently, only the weights of the tumors that were detected in vivo based on their mPlum signal correlated with FI. In conclusion, as long as tumors are visualized by their fluorescence signal the FI can be used to evaluate tumor burden. Deep-red FPs are more suitable for in vivo applications as compared to eGFP and dsRed2.
Mixed lineage leukemia (MLL) fusion protein (FP)-induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild-type (WT) MLL, MLL-FPs, and other partners such as the chromatin-associated protein LEDGF and the transcription factor C-Myb to promote leukemogenesis. The newly solved co-crystal structure illustrating the menin-MLL interaction, coupled with the role of menin in recruiting both WT MLL and MLL-FPs to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL-FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain-containing Brd4-related pathways to sustain MLL-FP-induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL-FP leukemias.