Identification of a novel fusion <i>TBL1XR1–PDGFRB</i> in a patient with acute myeloid leukemia harboring the <i>DEK–NUP214</i> fusion and clinical response to dasatinib

Campregher, Paulo Vidal; Halley, Nathalia da Silva; Vieira, Gabriela Amaral; Fernandes, Juliana Folloni; Velloso, Elvira Deolinda Rodrigues Pereira; Ali, Siraj M.; Mughal, Tariq I.; Miller, Vincent A.; Mangueira, Cristóvão Luis Pitangueira; Odone, Vicente; Hamerschlak, Nelson

doi:10.1080/10428194.2017.1318437

Cited by 19 publications

(14 citation statements)

References 17 publications

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“…The dimerization activity of the LisH domain in TBL1XR1 contributes to homodimerization and the dominant negative effect of RARs. Interestingly, the deletion and mutations in TBL1XR1 have been reported in various malignancies (24), and a previous study showed that TBL1XR1 was a component of the protein complex regulating the retinoic acid pathway (25). Considering an interesting result that one case had a mutation of TBL1XR1, alteration of TBL1XR1 may simultaneously contribute to the pathogenesis of APL.…”

Section: Discussionmentioning

confidence: 99%

Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

et al. 2018

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Translocations of retinoic acid receptor-α (), typically , are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of, we focused here on APL cases without translocation to elucidate the molecular etiology of-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without translocations. Four of five-negative APL cases had translocations involving retinoic acid receptor-β () translocations, and was identified as an in-frame fusion in three cases; one case had an rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as did. However, the response of APL with translocation to retinoids was attenuated compared with that of , an observation in line with the clinical resistance of-positive APL to ATRA. Our results demonstrate that the majority of -negative APL have translocations, thereby forming a novel, distinct subgroup of APL. as an oncogenic protein exerts effects similar to those of, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL. These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. .

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Section: Discussionmentioning

confidence: 99%

Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

et al. 2018

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“…KLF4- P53-KL4-CEBPA -axis has also been shown to activate CEBPA gene transcription via p53 [ 63 ]. HDAC1 has been shown to modulate KLF4 expression, suggesting HDAC1 and KLF4 as potential new molecular markers and targets for clinical diagnosis, prognosis, and treatment of myeloid leukemia [ 64 ]; TBL1XR1 is a fusion partner of several genes in leukemias such as TBL1XR1-RARA fusion in APL, TBL1XR1-ROS1 fusions in JMML, TBL1XR1-PDGFRB , a novel fusion in AML patients with DEK-NUP214 fusion [ 65 ]. TBL1XR1 is also identified as a recurrent abnormality in ETV6-RUNX1 positive ALL.…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML

Lamba

Cao

Raimondi

et al. 2020

Cancers

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Acute Myeloid Leukemia (AML) is characterized by recurrent genetic and cytogenetic lesions that are utilized for risk stratification and for making treatment decisions. In recent years, methylation dysregulation has been extensively studied and associated with risk groups and prognosis in adult AML, however, such studies in pediatric AML are limited. Moreover, the mutations in epigenetic genes such as DNMT3A, IDH1 or IDH2 are almost absent or rare in pediatric patients as compared to their abundance in adult AML. In the current study, we evaluated methylation patterns that occur with or independent of the well-defined cytogenetic features in pediatric AML patients enrolled on multi-site AML02 clinical trial (NCT00136084). Our results demonstrate that unlike adult AML, cytosine DNA methylation does not result in significant unique clusters in pediatric AML, however, DNA methylation signatures correlated significantly with the most common and recurrent cytogenetic features. Paired evaluation of DNA methylation and expression identified genes and pathways of biological relevance that hold promise for novel therapeutic strategies. Our results further demonstrate that epigenetic signatures occur complimentary to the well-established chromosomal/mutational landscape, implying that dysregulation of oncogenes or tumor suppressors might be leveraging both genetic and epigenetic mechanisms to impact biological pathways critical for leukemogenesis.

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“…The protein encoded by this gene composes an integral subunit of both nuclear receptor corepressor and histone deacetylase 3 complexes, and serves an essential role in regulating the activation of transcriptional and intracellular signaling pathways, such as JNK and ribonuclease pathways (21,22). Upregulation of TBL1XR1 gene expression has been observed in various cancer cell lines and solid tumors from patients (23,24), lymphoma (25) and acute leukemia (26), and are associated with advanced tumor stage, metastasis and poor prognosis. In SCC, elevated mRNA and protein expression of TBL1XR1 was confirmed in cells lines and patient samples (27).…”

Section: Discussionmentioning

confidence: 99%

HSP90AA1, ADRB2, TBL1XR1 and HSPB1 are chronic obstructive pulmonary disease‑related genes that facilitate squamous cell lung cancer progression

et al. 2020

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Chronic obstructive pulmonary disease (COPD) and squamous cell lung carcinoma (SCC) are smoking-related diseases. However, the connection between the two is poorly understood. Microarray gene expression profiles in bronchial epithelium from patients with SCC with or without COPD were downloaded from the Gene Expression Omnibus repository. Differentially expressed genes associated with COPD and SCC were identified and visualized using the Advanced Network Merger module in Cytoscape. COPD-associated genes in SCC progression were further identified using the BisoGenet plug-in in Cytoscape. The genetic interaction network was predicted using the Network Analysis function. Heat shock protein 90 α family class A member 1 (HSP90AA1), adrenoceptor β2 (ADRB2), transducin β like 1 X-linked receptor 1 (TBL1XR1) and heat shock protein family B (small) member 1 (HSPB1) were identified to be differentially expressed in SCC and COPD cases. The overall survival rate associated with the gene signatures was investigated using clinical samples from patients with SCC and COPD from the PROGgene database. The results suggest that the pathogenesis of SCC caused by COPD is regulated by HSP90AA1, ADRB2, TBL1XR1 and HSPB1. These genes may serve as potential therapeutic targets for the treatment of patients with COPD-related SCC.

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Identification of a novel fusion TBL1XR1–PDGFRB in a patient with acute myeloid leukemia harboring the DEK–NUP214 fusion and clinical response to dasatinib

Cited by 19 publications

References 17 publications

Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

DNA Methylation Clusters and Their Relation to Cytogenetic Features in Pediatric AML

HSP90AA1, ADRB2, TBL1XR1 and HSPB1 are chronic obstructive pulmonary disease‑related genes that facilitate squamous cell lung cancer progression

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