scholarly journals Elucidation of Novel Therapeutic Targets for Acute Myeloid Leukemias with RUNX1-RUNX1T1 Fusion

2019 ◽  
Vol 20 (7) ◽  
pp. 1717 ◽  
Author(s):  
Jae Yun ◽  
Yoon Bae ◽  
So Cho ◽  
Harim Koo ◽  
Hee-Jin Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fusion Protein ◽  
Signaling Pathways ◽  
Fusion Gene ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
The Cancer Genome Atlas ◽  
In Vitro Proliferation ◽  
Myeloid Leukemias ◽  
Acute Myeloid

The RUNX1-RUNX1T1 fusion is a frequent chromosomal alteration in acute myeloid leukemias (AMLs). Although RUNX1-RUNX1T1 fusion protein has pivotal roles in the development of AMLs with the fusion, RUNX1-RUNX1T1, fusion protein is difficult to target, as it lacks kinase activities. Here, we used bioinformatic tools to elucidate targetable signaling pathways in AMLs with RUNX1-RUNX1T1 fusion. After analysis of 93 AML cases from The Cancer Genome Atlas (TCGA) database, we found expression of 293 genes that correlated to the expression of the RUNX1-RUNX1T1 fusion gene. Based on these 293 genes, the cyclooxygenase (COX), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) pathways were predicted to be specifically activated in AMLs with RUNX1-RUNX1T1 fusion. Moreover, the in vitro proliferation of AML cells with RUNX1-RUNX1T1 fusion decreased significantly more than that of AML cells without the fusion, when the pathways were inhibited pharmacologically. The results indicate that novel targetable signaling pathways could be identified by the analysis of the gene expression features of AMLs with non-targetable genetic alterations. The elucidation of specific molecular targets for AMLs that have a specific genetic alteration would promote personalized treatment of AMLs and improve clinical outcomes.

Glioblastoma: Biology, Genetics, and Behavior

2012 ◽  
pp. 102-107 ◽  
Author(s):  
Daniel J. Brat
Keyword(s):  
Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Genetic Associations ◽  
Global Pattern ◽  
The Road ◽  
Peripheral Expansion

Overview: Glioblastoma (GBM) is a highly malignant, rapidly progressive astrocytoma that is distinguished pathologically from lower-grade tumors by necrosis and microvascular hyperplasia. The global pattern of growth changes dramatically with the development of GBM histology and is characterized by hypoxia-driven peripheral expansion from a growing necrotic core. Necrotic foci present centrally in GBM and are typically surrounded by “pseudopalisading” cells—a configuration that is relatively unique and long recognized as an ominous prognostic feature. Theses pseudopalisades are severely hypoxic, overexpress hypoxia inducible factor-1 (HIF-1), and secrete proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8). The microvascular hyperplasia that emerges in response promotes peripheral tumor expansion. Recent evidence suggests that pseudopalisades represent a wave of tumor cells actively migrating away from central hypoxia that arises following a vascular insult. Vaso-occlusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisading necrosis in tissue sections, the rapid peripheral expansion on neuroimaging, and the dramatic shift to an accelerated rate of clinical progression as a result of hypoxia-induced angiogenesis. The genetic alterations that coincide with progression to GBM include amplification of epidermal growth factor receptor (EGFR), deletion of CDKN2A, and mutation or deletion of PTEN. Other diagnostic and prognostic tests used in neuro-oncology include assessment of 1p/19q, MGMT promoter methylation, IDH1, and p53. More recently, the Cancer Genome Atlas data have indicated that there are four robust transcriptional classes of GBM, referred to as proneural, neural, classical, and mesenchymal. These classes have genetic associations and may pave the road for future development of targeted therapies.

scholarly journals Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1742
Author(s):  
Melysa Fitriana ◽  
Wei-Lun Hwang ◽  
Pak-Yue Chan ◽  
Tai-Yuan Hsueh ◽  
Tsai-Tsen Liao
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Cancer Stemness ◽  
Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

scholarly journals Frequency of EGFR Mutation and EML4-ALK fusion gene in Arab Patients with Adenocarcinoma of the Lung

2015 ◽  
Vol 6 (2) ◽  
pp. 19-23
Author(s):  
Hanan Ezzat Shafik ◽  
Mohamed Ashour
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egfr Mutation ◽  
Fusion Gene ◽  
Receptor Gene ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Anaplastic Lymphoma ◽  
Epidermal Growth

Abstract Introduction: Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. The frequency of epidermal growth factor receptor (EGFR) mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites, while the incidence of EML4-ALK (echinoderm microtubule-associated-protein like 4-anaplastic lymphoma kinase) fusion gene ranged from 1.6% to 16.4% in patients with NSCLC and these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. This study was conducted to determine the frequency of EGFR mutation and EML4-ALK fusion gene in our population and to determine the effect of different clinicopathological features on the expression of those mutations in patients with lung adenocarcinoma. Results: EGFR mutations were detected in approximately 33% of our patients in this series; the most frequently detected mutation was exon 19 deletion. EML4-ALK fusion gene was detected in 7.3% of patients. Conclusion: Our population exhibited the incidence of EGFR mutation approximately similar to that reported in East Asia and Japanese patients, higher than that recorded in USA, and Australia. However, more studies with larger patients’ numbers are needed to verify this finding.

scholarly journals Characterization and Use of an Antibody Detecting the CBFβ-SMMHC Fusion Protein in inv(16)/t(16;16)-Associated Acute Myeloid Leukemias

Blood ◽  
1998 ◽  
Vol 91 (6) ◽  
pp. 1882-1890
Author(s):  
David S. Viswanatha ◽  
I.-Ming Chen ◽  
Pu Paul Liu ◽  
Marilyn L. Slovak ◽  
Cathy Rankin ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Fusion Protein ◽  
Fusion Gene ◽  
Type A ◽  
Detection Methods ◽  
Rt Pcr ◽  
Cytogenetic Abnormalities ◽  
Permeabilized Cells ◽  
Flow Cytometric ◽  
Acute Myeloid

The inv(16)(p13q22) and t(16;16)(p13;q22) cytogenetic abnormalities occur commonly in acute myeloid leukemia (AML), typically associated with French-American-British (FAB) AML-M4Eo subtype. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques have been recently developed to detect the presence of several variants of the resultant CBFB-MYH11 fusion gene that encodes a CBFβ-smooth muscle myosin heavy chain (SMMHC) fusion protein. We have now determined the clinical use of a polyclonal antibody [anti-inv(16) Ab] directed against a junctional epitope of the most common type of CBFβ-SMMHC fusion protein (type A), which is present in 90% of inv(16)/t(16;16) AML cases. Using flow cytometry, reproducible methods were developed for detection of CBFβ-SMMHC proteins in permeabilized cells; flow cytometric results were then correlated with cytogenetics and RT-PCR detection methods. In an analysis of 42 leukemia cases with various cytogenetic abnormalities and several normal controls, the anti-inv(16) Ab specifically detected all 23 cases that were cytogenetically positive for inv(16) or t(16;16), including a single AML case that was RT-PCR–negative. In addition to detecting all type A fusions, the anti-inv(16) Ab also unexpectedly identified the type C and type D CBFβ-SMMHC fusion proteins. Molecular characterization of one RT-PCR–positive and Ab-positive t(16;16) case with a non-type A product showed a novel previously unreported CBFB-MYH11 fusion (CBFB nt 455-MYH11 nt 1893). Flow cytometric results were analyzed using the Kolmogorov-Smirnov statistic D-value and the median value for positive samples was 0.65 (range, 0.35 to 0.77) versus 0.07 (range, −0.21 to 0.18) in the negative group (P < .0001). The overall concordance between cytogenetics and RT-PCR was 97%, whereas the concordance between flow cytometry and cytogenetics was 100%. Thus, using the anti-inv(16) Ab, all cytogenetically positive and RT-PCR–positive AML cases with inv(16) or t(16;16) could be rapidly identified. This study demonstrates the use of this antibody as an investigational tool in inv(16)/t(16;16) AML and suggests that the development of such reagents may have potential clinical diagnostic use.

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