Research IndicatorsGraph generated 01 September 2019 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
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
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: MECOM (cancer-related)
Ectopic Viral Integration site 1 (EVI1) upregulation is implicated in 10-25% of pediatric acute myeloid leukemia (AML) and has an inferior outcome with current chemotherapy regimens. Here we report that EVI1 upregulation is associated with methylation of the miR-9 promoter and correlated with downregulation of miR-9 in human AML cell lines and bone marrow (BM) cells from pediatric patients. Reactivation of miR-9 by hypomethylating agents and forced expression of miR-9 in EVI1
BACKGROUND: Aberrant EVI1 expression is frequently reported in cancer studies; however, its role in nasopharyngeal carcinoma (NPC) has not been examined in detail. The aim of the present study is to investigate the involvement of EVI1 in progression and prognosis of NPC.
METHODS: RT-PCR, immunohistochemistry and western blot assays were used to examine the expression of EVI1 in NPC tissues and cell lines. Fluorescence in situ hybridization assay was used to examine the amplification of EVI1 in NPC tissues. The biological effect of EVI1 was determined by both in vitro and in vivo studies. The dual-luciferase reporter assay was performed to confirm that EVI1 bind at E-cadherin andβ-catenin promoters. The ChIP, EMSA, and coimmunoprecipitation combined with mass spectrometry assays were used to analyze the EVI1 regulated proteins.
RESULTS: EVI1 expression level was up-regulated in NPC tissues and cell lines. EVI1 was amplificated in NPC tissues. We observed that EVI1 down-regulation decreased the cell proliferation and invasive capacity of NPC cells in vitro and in vivo. EVI1, snail, and HDAC1 formed a co-repressor complex to repress E-cadherin expression and ultimately contributed to epithelial mesenchymal transition (EMT) phenotype in NPC cells. In another way, EVI1 directly bound at β-catenin promoter and activated its expression. β-catenin mediated EVI1's function on cancer stem cells (CSCs) properties. EVI1 up-regulation predicted unfavorable prognosis and contributed to chemo/radio-resistance in NPC cells. Finally, we constructed arsenic trioxide-loaded nanoparticles (ALNPs) and revealed that ALNPs exerted anti-tumor effect in NPC cells.
CONCLUSIONS: Our data indicated that EVI1 played an oncogenic role in NPC growth and metastasis and that EVI1 might serve as a novel molecular target for the treatment of NPC.
RATIONALE: Acute lymphoblastic leukemia (ALL) secondary to multiple myeloma (MM) is rare. Here we report a rare case of secondary ALL transformed from MM.
PATIENT CONCERNS: A 64-year-old woman was diagnosed as MM IgG light chain type in 2001. She achieved complete remission after 2 cycles of therapy, and received maintenance therapy with thalidomide. The patient suffered from MM relapse in September 2011. Bone marrow examination showed that the percentage of primary lymphocytes was 59%, indicating ALL-L2 (Pre-B-ALL). The patient reached complete remission after 1 cycle of chemotherapy, and has been maintained for more than 6 years.
DIAGNOSES: Immunophenotyping analysis revealed that the abnormal cell population accounted for approximately 66% which expressed HLA-DR, CD4, CD22, CD33, CD34, and cCD79a. These results indicated acute B lymphoblastic leukemia. Chromosome presented 47, XX, +5, -7, +19. Leukemia fusion gene analysis demonstrated positive EVI1 and negative IgH and TCR gene rearrangement.
INTERVENTIONS: The patient accepted 1 cycle of VDCLP chemotherapy and reached complete remission, followed with consolidation therapies with VDCLP, MA, CAG and other chemotherapy regimens.
OUTCOMES: This patient has maintained CR1 of ALL for more than 6 years.
LESSONS: Even secondary lymphoblastic leukemia has been rarely reported in patients with MM, we still need perform bone marrow examination, flow cytology, and gene tests, especially during maintenance therapy.
Ecotropic viral integration site‑1 (EVI‑1) is an important transcription factor involved in oncogenesis. Aberrant EVI‑1 expression has been reported to be a characteristic of multiple types of malignancies; however, very little is known about how EVI‑1 regulates breast cancer. Current knowledge of how target genes mediate the biological function of EVI‑1 remains limited. In the present study, overexpression of EVI‑1 promoted cell proliferation, migration, and invasion, and inhibited apoptosis in breast cancer. By contrast, silencing of EVI‑1 inhibited cell proliferation, migration and invasion, and enhanced apoptosis in breast cancer. In addition, the results also revealed that the aberrant expression of EVI‑1 regulates genes associated with the apoptotic pathway in breast cancer. Furthermore, EVI‑1 was also likely to target the promoter region of calreticulin (CRT) in vitro. It was concluded that EVI‑1 can affect epithelial mesenchymal transition‑associated genes by regulating the expression of CRT in breast cancer. The results revealed that EVI‑1 may be a potential effective therapeutic target in breast cancer.
Hodge JC, Bosler D, Rubinstein L, et al.Molecular and pathologic characterization of AML with double Inv(3)(q21q26.2).
Cancer Genet. 2019; 230:28-36 [PubMed
] Related Publications
The inv(3)(q21q26.2) altering a single chromosome 3 homolog is an established myeloid malignancy-associated entity. Comparatively, double inv(3) cases involving both homologs are exceedingly rare with 13 reports across AML, CML and MDS. This scarcity was confirmed by finding only 2 new cases out of 34,898 bone marrows collected during a 55 year period at a large medical center (0.0005%). The double inv(3) was detected by karyotype and confirmed by FISH on both homologs in a 41 year old female and a 72 year old male with AML. In the latter case, a 2.26-fold increase in MECOM RNA level was found using an NGS myeloid gene panel. Chromosomal microarray analysis identified segmental copy-neutral loss-of-heterozygosity (CN-LOH) at 3q21 extending to near the q-arm terminus. This is the third report of distal 3q CN-LOH, substantiating that the double inv(3) arises through somatic repair of acquired segmental LOH. Long term clinical and genetic evaluation revealed no discernible morphologic difference between single and double inv(3) cases, conventional chemotherapy resistance and rapid dominance of the double inv(3) clone. The two new cases are consistent with relatively longer survival of double inv(3) patients in the absence of concurrent chromosome 7 loss compared to those with both abnormalities. Importantly, the first known outcome data of bone marrow transplantation in double inv(3) AML is also presented.
The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number of zinc-finger motifs, which likely mediate protein⁻protein, protein⁻RNA, or protein⁻DNA interactions. Intriguingly, almost all PRDM family members express different isoforms, which likely play opposite roles in oncogenesis. Remarkably, several studies have described alterations in most of the family members in malignancies. Here, to obtain a pan-cancer overview of the genomic and transcriptomic alterations of
Paredes R, Schneider M, Stevens A, et al.EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.
Nucleic Acids Res. 2018; 46(15):7662-7674 [PubMed
] Free Access to Full Article Related Publications
The transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. In the presence of genotoxic stress EVI1-WT (SQS), but not site mutated EVI1-AQA was able to maintain transcriptional patterns and transformation potency, while under standard conditions carboxy-terminal mutation had no effect. Maintenance of hematopoietic progenitor cell clonogenic potential was profoundly impaired with EVI1-AQA compared with EVI1-WT, in particular in the presence of genotoxic stress. Exploring mechanistic events underlying these observations, we showed that after genotoxic stress EVI1-WT, but not EVI1-AQA increased its level of association with its functionally essential interaction partner CtBP1, implying a role for ATM in regulating EVI1 protein interactions via phosphorylation. This aspect of EVI1 regulation is therapeutically relevant, as chemotherapy-induced genotoxicity might detrimentally sustain EVI1 function via stress response mediated phosphorylation, and ATM-inhibition might be of specific targeted benefit in EVI1-overexpressing malignancies.
Lang WJ, Chen FYThe reciprocal link between EVI1 and miRNAs in human malignancies.
Gene. 2018; 672:56-63 [PubMed
] Related Publications
Ecotropic virus integration site-1 (EVI1) is an oncogenic transcription factor which locus on chromosome 3(3q26.2). Alterations in EVI1 functions correspond with poor prognosis in different cancers, underscoring their status for the clinical cancer phenotype. MicroRNAs(MiR)are a class of small non-coding RNA sequences. They post-transcriptionally influence mRNA sequence through imperfect pairing with the 3'-UTR. Moreover, a growing body of studies showed that miRNAs could regulate initiation and progression of human malignancies. Current studies have been described that identifies numerous microRNAs that can be modulated by EVI1. Interestingly, the expression level of EVI1 can also be regulated by microRNAs, thus forming a reciprocal link. Recent understanding of the functional roles of EVI1, microRNAs, and their interactions in human cancers are summarized. This review will help to define a relationship between EVI1 and microRNAs in human malignancies and develop novel therapeutic strategies.
SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel-Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel-Giedion syndrome caused by SETBP1 mutations.
Suguna E, Farhana R, Kanimozhi E, et al.Acute Myeloid Leukemia: Diagnosis and Management Based on Current Molecular Genetics Approach.
Cardiovasc Hematol Disord Drug Targets. 2018; 18(3):199-207 [PubMed
] Related Publications
BACKGROUND & OBJECTIVE: Acute Myeloid Leukemia (AML) is characterized by the accumulation of ≥20% myeloid premature blast cells in the bone marrow and they are most often found in the peripheral blood. AML is generally classified based on either French-American-British (FAB) or World Health Organization (WHO) systems. For better clinical management, cytogenetic finding in AML is necessary and in patients with normal karyotypes - molecular, epigenetic and proteomic biomarkers are very important in choosing which drugs to prescribe. Mutations of certain genes like NPM1, FLT3, CEBPA, RUNX1 and MLL play a crucial role in the risk management and clinical stratification of AML patients. We reviewed the literature for the current trends of clinical practice based on laboratory based diagnostic tests in AML. Outcome and Result: We listed in AML chromosomal aberrations (translocations, fusions or RUNX1, CBFB, MYHI1, MLL, EVI1, PML-RARA), genes and mutations (NPM1, FLT3, CEPBA, MLL) epigenetic factors (DNMT34, TET2) and proteomic biomarkers (PTP, PTK, PIP) and analysed how on the basis of these factors medical risk was stratified and accordingly managed.
CONCLUSION: AML is genetically and functionally a heterogenous malignant disease. In the western world, leukemia is one of the most common among all cancers. India is ranked 3rd in cancer disease after United States of America and China. Cytogenetic analysis, molecular/proteomic biomarkers and epigenetic factors assist in determining the management strategies and prognosis of the disease. A number of targeted drugs in pre-clinical and clinical trials based on molecular factors and epigenetic mechanisms have been reported to have promising results in AML patients.
Han Q, Lu J, Wang J, et al.H2AFY is a novel fusion partner of MECOM in acute myeloid leukemia.
Cancer Genet. 2018; 222-223:9-12 [PubMed
] Related Publications
The MECOM gene encoding a zinc finger protein that functions as a transcription factor, was located on chromosome 3q26, and rearrangements of MECOM often cause its overexpression in acute myeloid leukemia (AML). We identified H2AFY as a novel fusion gene partner of MECOM in an elderly male AML patient with cryptic 3q26 rearrangement using the whole transcriptome sequencing, who carried out abnormal karyotype of 46,XY,t(3;5)(q27;q31),add(14)(p11). We validated the existence of the unreported H2AFY-MECOM fusion gene by RT-PCR and Sanger DNA sequencing, and detected mutations of NRAS and BCOR in this patient. In addition, we found abnormally elevated expression of MECOM in this patient by quantitative-polymerase chain reaction (RQ-PCR). Further research is needed to investigate functional characterizations of this novel fusion in the development of AML.
Adams T, Fuchs D, Shadoan PK, et al.Unexpected favorable outcome in a patient with high grade B-cell lymphoma with abnormalities of MYC, BCL6 and BCL2 loci.
Cancer Genet. 2018; 222-223:25-31 [PubMed
] Related Publications
High grade B-cell lymphoma (HGBCL) by WHO 2016 classification requires rearrangements of MYC and BCL2 and/or BCL6, practically covering the so called "double-hit" or "triple hit" lymphomas. We report a case of HGBCL "triple-hit" lymphoma in a 64-year old female. Cytogenetic and fluorescence in situ hybridization (FISH) studies revealed complex karyotype including rearrangement of MYC to a novel, non-IG partner on chromosome 18, and rearrangement of BCL2, BCL6 and IGH as well as ins(3)(q21q27.3q25.1) among other abnormalities. FISH studies showed five copies of MYC and 3-8 copies of BCL2. Gene expression analysis by RNA sequencing showed that MYC, BCL2 and MECOM genes were overexpressed whereas BCL6 was under-expressed. BCL6 was fused to MBNL1 gene due to complex structural rearrangement. MYC was expressed in >70% of cells and BCL2 was diffusely but highly expressed by immunohistochemistry. No pathogenic mutations were identified by sequencing a 26-gene panel including TP53. The patient has unexpectedly been in complete remission for 12 months after diagnosis after intensive chemotherapy including DA-EPOCH regimen despite having HGBCL. The prognostication of HGBCL patients may further be improved by the sub-categorization of these lymphomas on the basis of more detailed genomic markers than merely the WHO 2016 classification.
Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic
Shahrabi S, Behzad MM, Jaseb K, Saki NThrombocytopenia in leukemia: Pathogenesis and prognosis.
Histol Histopathol. 2018; 33(9):895-908 [PubMed
] Related Publications
Leukemias, a heterogeneous group of hematological disorders, are characterized by ineffective hematopoiesis and morphologic abnormalities of hematopoietic cells. Thrombocytopenia is a common problem among leukemia types that can lead to hemorrhagic complications in patients. The purpose of this review article is to identify the conditions associated with the incidence of thrombocytopenia in leukemias. It can be stated that although translocations have been considered responsible for this complication in many studies, other factors such as bone marrow failure, genes polymorphism, a mutation in some transcription factors, and the adverse effects of treatment could be associated with pathogenesis and poor prognosis of thrombocytopenia in leukemias. Considering the importance of thrombocytopenia in leukemias, it is hoped that the recognition of risk factors increasing the incidence of this complication in leukemic patients would be useful for prevention and treatment of this disorder.
Acute myeloid leukemia (AML) is a heterogeneous disease caused by recurrent mutations in the transcription regulatory machinery, resulting in abnormal growth and a block in differentiation. One type of recurrent mutations affects
Dzneladze I, Woolley JF, Rossell C, et al.SubID, a non-median dichotomization tool for heterogeneous populations, reveals the pan-cancer significance of INPP4B and its regulation by EVI1 in AML.
PLoS One. 2018; 13(2):e0191510 [PubMed
] Free Access to Full Article Related Publications
Our previous studies demonstrated that INPP4B, a member of the PI3K/Akt signaling pathway, is overexpressed in a subset of AML patients and is associated with lower response to chemotherapy and shorter survival. INPP4B expression analysis in AML revealed a right skewed frequency distribution with 25% of patients expressing significantly higher levels than the majority. The 75% low/25% high cut-off revealed the prognostic power of INPP4B expression status in AML, which would not have been apparent with a standard median cut-off approach. Our identification of a clinically relevant non-median cut-off for INPP4B indicated a need for a generalizable non-median dichotomization approach to optimally study clinically relevant genes. To address this need, we developed Subgroup Identifier (SubID), a tool which examines the relationship between a continuous variable (e.g. gene expression), and a test parameter (e.g. CoxPH or Fisher's exact P values). In our study, Fisher's exact SubID was used to reveal EVI1 as a transcriptional regulator of INPP4B in AML; a finding which was validated in vitro. Next, we used CoxPH SubID to conduct a pan-cancer analysis of INPP4B's prognostic significance. Our analysis revealed that INPP4Blow is associated with shorter survival in kidney clear cell, liver hepatocellular, and bladder urothelial carcinomas. Conversely, INPP4Blow was shown to be associated with increased survival in pancreatic adenocarcinoma in three independent datasets. Overall, our study describes the development and application of a novel subgroup identification tool used to identify prognostically significant rare subgroups based upon gene expression, and for investigating the association between a gene with skewed frequency distribution and potentially important upstream and downstream genes that relate to the index gene.
BACKGROUND Acute myeloid leukemia with intermediate cytogenetic risk (ICR-AML) needs to be stratified. The abnormal gene expression might be prognostic, and its cutoff value for patient grouping is pivotal. MATERIAL AND METHODS Ecotropic viral integration site 1 (EVI1) transcripts were assessed in 191 adult ICR-AML patients at diagnosis who received chemotherapy only. MLL-PTD, WT1 transcript levels, FLT3-ITD, and NPM1 mutations were simultaneously evaluated, and 27 normal bone marrow samples were tested to define normal threshold. RESULTS The normal upper limit of EVI1 transcript levels was 8.0%. Receiver operating characteristic curve analysis showed that 1.0% (a 0.9-log reduction from the normal limit) was the EVI1 optimal cutoff value for significantly differentiating relapse (P=0.049). A total of 23 patients (12%) had EVI1 levels ≥1.0%. EVI1 ≥1.0% had no effect on CR achievement, whereas it was significantly associated with lower 2-year relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS) rates in the entire cohort (P=0.0003, 0.0017, and 0.0009, respectively), patients with normal karyotypes (P=0.0032, 0.0047, and 0.0007, respectively), and FLT3-ITD (-) patients (all P<0.0001). Multivariate analysis showed that EVI1 ≥1.0% was an independent adverse prognostic factor for RFS, DFS, and OS in the entire cohort. In addition, patients with EVI1 transcript levels between 1.0% and 8.0% had 2-year RFS rates similar to those with EVI1 ≥8.0%, and they both had significantly lower RFS rates than those with EVI1 <1.0% (P=0.0005 and 0.027). CONCLUSIONS High EVI1 expression predicts poor outcome in ICR-AML patients receiving chemotherapy. The optimal cutoff value for patient stratification is different from the normal limit.
Burillo-Sanz S, Morales-Camacho RM, Caballero-Velázquez T, et al.MLL-rearranged acute myeloid leukemia: Influence of the genetic partner in allo-HSCT response and prognostic factor of MLL 3' region mRNA expression.
Eur J Haematol. 2018; 100(5):436-443 [PubMed
] Related Publications
OBJECTIVE: MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected gene's expression, in this work, we have studied a cohort of 20 MLL-rearranged acute myeloid leukemia (AML).
METHODS: Twenty MLL-rearranged AML patients along with a control cohort of 138 AML patients are included in this work. By RT-PCR and sequencing, MLL genetic fusion was characterized, and relative gene expression quantification was carried out for EVI1, MEIS1, MLL-3', RUNX1, SETBP1, HOXA5, and FLT3 genes. Risk stratification and association of MLL genetic partner and gene expression to overall survival, in the context of received therapy, were performed.
RESULTS: MLLr cohort showed to have an OS more similar to intermediate-risk AML. Type of MLL genetic partner showed to be relevant in allo-HSCT response; having MLLT1 and MLLT3, a better benefit from it. Expression of MLL-3' region, EVI1 and FLT3, showed association with OS in patients undergoing allo-HSCT.
CONCLUSION: We show that the MLL genetic partner could have implications in allo-HSCT response, and we propose three genes whose expression could be useful for the prognosis of this leukemia in patients undergoing allo-HSCT: 3' region of MLL, EVI1, and FLT3.
The most indecipherable component of solid cancer is the development of metastasis which accounts for more than 90% of cancer-related mortalities. A developmental program termed epithelial-mesenchymal transition (EMT) has also been shown to play a critical role in promoting metastasis in epithelium-derived solid tumors. By analyzing publicly available microarray datasets, we observed that ecotropic viral integration site 1 (EVI1) correlates negatively with SLUG, a master regulator of EMT. This correlation was found to be relevant as we demonstrated that EVI1 binds to SLUG promoter element directly through the distal set of zinc fingers and downregulates its expression. Many studies have shown that the primary role of SLUG during EMT and EMT-like processes is the regulation of cell motility in most of the cancer cells. Knockdown of EVI1 in metastatic colon cancer cell and subsequent passage through matrigel not only increased the invading capacity but also induced an EMT-like morphological feature of the cells, such as spindle-shaped appearance and led to a significant reduction in the expression of the epithelial marker, E-CADHERIN and increase in the expression of the mesenchymal marker, N-CADHERIN. The cells, when injected into immunocompromised mice, failed to show any metastatic foci in distant organs however the ones with EVI1, metastasized in the intraperitoneal layer and also showed multiple micro metastatic foci in the lungs and spleen. These findings suggest that in colon cancer EVI1 is dispensable for epithelial-mesenchymal transition, however, is required for metastasis.
AIM: To identify chromosomal copy number aberrations (CNAs) in early-stage hepatocellular carcinoma (HCC) and analyze whether they are correlated with patient prognosis.
METHODS: One hundred and twenty patients with early-stage HCC were enrolled in our study, with the collection of formalin fixed, paraffin-embedded (FFPE) specimens and clinicopathological data. Tumor areas were marked by certified pathologists on a hematoxylin and eosin-stained slide, and cancer and adjacent non-cancerous tissues underwent extraction of DNA, which was analyzed with the Affymetrix OncoScan platform to assess CNAs and loss of heterozygosity (LOH). Ten individuals with nonmalignant disease were used as the control group. Another cohort consisting of 40 patients with stage I/II HCC were enrolled to analyze gene expression and to correlate findings with the OncoScan data.
RESULTS: Copy number amplifications occurred at chromosomes 1q21.1-q44 and 8q12.3-24.3 and deletions were found at 4q13.1-q35.2, 8p 23.2-21.1, 16q23.3-24.3, and 17p13.3-12, while LOH commonly occurred at 1p32.3, 3p21.31, 8p23.2-21.1, 16q22.1-24.3, and 17p 13.3-11 in early-stage HCC. Using Cox regression analysis, we also found that a higher percentage of genome change (≥ 60%) was an independent factor for worse prognosis in early-stage HCC (
CONCLUSION: Patients with early-stage HCC and increased genome change or CNAs involving
Kotaki R, Higuchi H, Ogiya D, et al.Imbalanced expression of polycistronic miRNA in acute myeloid leukemia.
Int J Hematol. 2017; 106(6):811-819 [PubMed
] Related Publications
miR-1 and miR-133 are clustered on the same chromosomal loci and are transcribed together as a single transcript that is positively regulated by ecotropic virus integration site-1 (EVI1). Previously, we described how miR-133 has anti-tumorigenic potential through repression of EVI1 expression. It has also been reported that miR-1 is oncogenic in the case of acute myeloid leukemia (AML). Here, we show that expression of miR-1 and miR-133, which have distinct functions, is differentially regulated between AML cell lines. Interestingly, the expression of miR-1 and EVI1, which binds to the promoter of the miR-1/miR-133 cluster, is correlative. The expression levels of TDP-43, an RNA-binding protein that has been reported to increase the expression, but inhibits the activity, of miR-1, were not correlated with expression levels of miR-1 in AML cells. Taken together, our observations raise the possibility that the balance of polycistronic miRNAs is regulated post-transcriptionally in a hierarchical manner possibly involving EVI1, suggesting that the deregulation of this balance may play some role in AML cells with high EVI1 expression.
BACKGROUND: Cytogenetic aberrations and gene mutations have long been regarded as independent prognostic markers in AML, both of which can lead to misexpression of some key genes related to hematopoiesis. It is believed that the expression level of the key genes is associated with the treatment outcome of AML.
METHODS: In this study, we analyzed the clinical features and molecular aberrations of 560 newly diagnosed non-M3 AML patients, including mutational status of CEBPA, NPM1, FLT3, C-KIT, NRAS, WT1, DNMT3A, MLL-PTD and IDH1/2, as well as expression levels of MECOM, ERG, GATA2, WT1, BAALC, MEIS1 and SPI1.
RESULTS: Certain gene expression levels were associated with the cytogenetic aberration of the disease, especially for MECOM, MEIS1 and BAALC. FLT3, C-KIT and NRAS mutations contained conversed expression profile regarding MEIS1, WT1, GATA2 and BAALC expression, respectively. FLT3, DNMT3A, NPM1 and biallelic CEBPA represented the mutations associated with the prognosis of AML in our group. Higher MECOM and MEIS1 gene expression levels showed a significant impact on complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) both in univariate and multivariate analysis, respectively; and an additive effect could be observed. By systematically integrating gene mutational status results and gene expression profile, we could establish a more refined system to precisely subdivide AML patients into distinct prognostic groups.
CONCLUSIONS: Gene expression abnormalities contained important biological and clinical informations, and could be integrated into current AML stratification system.
Ghasemian Sorbeni F, Montazersaheb S, Ansarin A, et al.Molecular analysis of more than 140 gene fusion variants and aberrant activation of EVI1 and TLX1 in hematological malignancies.
Ann Hematol. 2017; 96(10):1605-1623 [PubMed
] Related Publications
Gene fusions are observed in abnormal chromosomal rearrangements such as translocations in hematopoietic malignancies, especially leukemia subtypes. Hence, it is critical to obtain correct information about these rearrangements in order to apply proper treatment techniques. To identify abnormal molecular changes in patients with leukemia, we developed a multiplex reverse transcriptase polymerase chain reaction (MRT-PCR) protocol and investigated more than 140 gene fusions resulting from variations of 29 prevalent chromosomal rearrangements along with EVI1 and TLX1 oncogenic expression in the presence of optimized primers. The potential of the MRT-PCR method was approved by evaluating the available cell lines as positive control and confirmed by sequencing. Samples from 53 patients afflicted with hematopoiesis malignancies were analyzed. Results revealed at least one chromosomal rearrangement in 69% of acute myeloid leukemia subjects, 64% of acute lymphoblastic leukemia subjects, and 81% of chronic myeloid leukemia subjects, as well as a subject with hypereosinophilic syndrome. Also, five novel fusion variants were detected. Results of this study also showed that chromosomal rearrangements, both alone and in conjunction with other rearrangements, are involved in leukemogenesis. Moreover, it was found that EVI1 is a suitable hallmark for hematopoietic malignancies.
BACKGROUND: Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients' therapy.
METHODS: Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA).
RESULTS: The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients' survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation.
CONCLUSION: Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment.
Yamato G, Yamaguchi H, Handa H, et al.Clinical features and prognostic impact of PRDM16 expression in adult acute myeloid leukemia.
Genes Chromosomes Cancer. 2017; 56(11):800-809 [PubMed
] Related Publications
High PRDM16 (also known as MEL1) expression is a representative marker of acute myeloid leukemia (AML) with NUP98-NSD1 and is a significant predictive marker for poor prognosis in pediatric AML. However, the clinical features of adult AML with PRDM16 expression remain unclear. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of MECOM (also known as EVI1). We investigated PRDM16 expression in 151 AML patients, with 47 (31%) exhibiting high PRDM16 expression (PRDM16/ABL1 ratio ≥ 0.010). High PRDM16 expression significantly correlated with DNMT3A (43% vs. 15%, P < 0.001) and NPM1 (43% vs. 21%, P = 0.010) mutations and partial tandem duplication of KMT2A (22% vs. 1%, P < 0.001). Remarkably, high-PRDM16-expression patients were frequent in the noncomplete remission group (48% vs. 21%, P = 0.002). Overall survival (OS) was significantly worse in high-PRDM16-expression patients than in low-PRDM16-expression patients (5-year OS, 18% vs. 34%; P = 0.002). This trend was observed more clearly among patients aged <65 years (5-year OS, 21% vs. 50%; P = 0.001), particularly in FLT3-ITD-negative patients in the intermediate cytogenetic risk group (5-year OS, 25% vs. 59%; P = 0.009). These results suggest that high PRDM16 expression is a significant predictive marker for poor prognosis in adult AML patients, similar to pediatric AML patients.
Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML.
Maicas M, Vázquez I, Alis R, et al.The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells.
Biochim Biophys Acta Gene Regul Mech. 2017; 1860(6):721-729 [PubMed
] Related Publications
Transcriptional activation of the EVI1 oncogene (3q26) leads to aggressive forms of human acute myeloid leukemia (AML). However, the mechanism of EVI1-mediated leukemogenesis has not been fully elucidated. Previously, by characterizing the EVI1 promoter, we have shown that RUNX1 and ELK1 directly regulate EVI1 transcription. Intriguingly, bioinformatic analysis of the EVI1 promoter region identified the presence of several EVI1 potential binding sites. Thus, we hypothesized that EVI1 could bind to these sites regulating its own transcription. In this study, we show that there is a functional interaction between EVI1 and its promoter, and that the different EVI1 isoforms (EVI1-145kDa, EVI1-Δ324 and MDS1-EVI1) regulate the transcription of EVI1 transcripts through distinct promoter regions. Moreover, we determine that the EVI1-145kDa isoform activates EVI1 transcription, whereas EVI1-Δ324 and MDS1-EVI1 act as repressors. Finally, we demonstrate that these EVI1 isoforms are involved in cell transformation; functional experiments show that EVI1-145kDa prolongs the maintenance of hematopoietic stem and progenitor cells; conversely, MDS1-EVI1 repressed hematopoietic stem and progenitor colony replating capacity. We demonstrate for the first time that EVI1 acts as a regulator of its own expression, highlighting the complex regulation of EVI1, and open new directions to better understand the mechanisms of EVI1 overexpressing leukemias.
Akhter A, Farooq F, Elyamany G, et al.Acute Myeloid Leukemia (AML): Upregulation of BAALC/MN1/MLLT11/EVI1 Gene Cluster Relate With Poor Overall Survival and a Possible Linkage With Coexpression of MYC/BCL2 Proteins.
Appl Immunohistochem Mol Morphol. 2018; 26(7):483-488 [PubMed
] Related Publications
BACKGROUND: Molecular heterogeneity accounts for the variable and often poor prognosis in acute myeloid leukemia (AML). The current risk stratification strategy in clinical practice is limited to karyotyping and limited molecular studies screening for genetic mutations such as FLT-3 and NPM1. There is opportunity to identify further molecular prognostic markers, which may also lay the groundwork for the development of novel targeted therapies. Complex molecular technologies require transition into widely available laboratory platforms, for better integration into routine clinical practice.
METHOD: In a defined subset (MYC/BCL2 or MYC/BCL2) of AML patients (n=20), we examined expression signature of several genes (n=12) of established prognostic value in AML. RNA expression and MYC/BCL2 protein pattern was correlated with 3 cytogenetic risk groups and overall survival.
RESULTS: K-means++ unsupervised clustering defined 2 distinct groups with high and low transcript levels of BAALC/MN1/MLLT11/EVI1/SOCS2 genes (>2.5-fold difference; P<0.001). This mRNA signature trended with higher prevalence of MYC/BCL2 coexpression (P<0.057) and poor overall survival (P<0.036), but did not correlate with conventional cytogenetic risk groups (P<0.084).
CONCLUSIONS: This pilot study provides useful data, which may help further refine the prognostic scheme of AML patients outside conventional cytogenetic risk groups. It also presents some biological rationale for future studies to explore the use of novel agents targeting MYC and/or BCL2 genes in combination with conventional chemotherapy protocols for AML.
Wang H, Schaefer T, Konantz M, et al.Prominent Oncogenic Roles of EVI1 in Breast Carcinoma.
Cancer Res. 2017; 77(8):2148-2160 [PubMed
] Related Publications
Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma where its contributions are unexplored. Analyzing a tissue microarray of 608 breast carcinoma patient specimens, we documented EVI1 overexpression in both estrogen receptor-positive (ER
Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.
Rubin CM, Larson RA, Anastasi J, et al.t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia.
Blood. 1990; 76(12):2594-8 [PubMed
] Related Publications
We have identified an identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints at bands 3q26 and 21q22, [t(3;21)(q26;q22)], in the malignant cells from five adult patients with therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Primary diagnoses were Hodgkin's disease in two patients and ovarian carcinoma, breast cancer, and polycythemia vera in one patient each. Patients had been treated with chemotherapy including an alkylating agent for their primary disease 1 to 18 years before the development of t-MDS or t-AML. We have not observed the t(3;21) in over 1,500 patients with a myelodysplastic syndrome or acute myeloid leukemia arising de novo or in over 1,000 patients with lymphoid malignancies. We have previously reported that the t(3;21) occurs in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Thus, the t(3;21) appears to be limited to t-MDS/t-AML and CML, both of which represent malignant disorders of an early hematopoietic precursor cell. These results provide a new focus for the study of therapy-related leukemia at the molecular level.