PAX5-KIAA1549L: a novel fusion gene in a case of pediatric B-cell precursor acute lymphoblastic leukemia

Anderl, Stefanie; König, Margit; Attarbaschi, Andishe; Strehl, Sabine

doi:10.1186/s13039-015-0138-3

Cited by 7 publications

(5 citation statements)

References 37 publications

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“…One cohort did not drive this association as post hoc analyses indicated the top SNP was associated at p< 0.05 in the same direction in both cohorts. The KIAA1549L protein, spanning 1,849 amino acids, contains highly conserved regions and had been shown to act as a fusion partner of paired box 5 ( PAX5 ), a transcription factor that is critical for B-cell activation and maintenance (Anderl et al, 2015; Medvedovic et al, 2011). PAX5 was one of the most associated genes with chronotype in a gene-based test from Lane and colleagues’ (2016) study of the UK Biobank sample.…”

Section: Discussionmentioning

confidence: 99%

Genetic Influences on Evening Preference Overlap with Those for Bipolar Disorder in a Sample of Mexican Americans and American Indians

et al. 2017

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Diurnal preference (e.g. being an “owl” or “lark”) has been associated with several psychiatric disorders including bipolar disorder (BP), major depressive disorder, and substance use disorders. Previous large-scale genome-wide association studies (GWAS) aimed at identifying genetic influences on diurnal preference have exclusively included subjects of European ancestry. This study examined the genetic architecture of diurnal preference in two minority samples: a young adult sample of Mexican Americans (MAs), and a family-based sample of American Indians (AIs). Typed or imputed variants from exome chip data from the MA sample and low pass whole-genome sequencing from the AI cohort were analyzed using a mixed linear model approach for association with being an owl, as defined by a usual bedtime after 23:00 hrs. Genetic risk score (GRS) profiling detected shared genetic risk between evening preference and related disorders. Four variants in KIAA1549 like (KIAA1549L), a gene previously associated with attempted suicide in bipolar patients, were suggestively associated with being an owl at p<1.82E-05; post hoc analyses showed the top variant trending in both the MA and AI cohorts at p=2.50E-05 and p=0.030, respectively. Variants associated with BP at p<0.03 from the Psychiatric Genomics Consortium nominally predicted being an owl in the MA/AI cohort at p=0.012. This study provides some additional evidence that genetic risk factors for BP also confer risk for being an owl in MAs/AIs and that evening preference may be a useful endophenotype for future studies of BP.

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Section: Discussionmentioning

confidence: 99%

Genetic Influences on Evening Preference Overlap with Those for Bipolar Disorder in a Sample of Mexican Americans and American Indians

et al. 2017

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“…1f ). Within the fusion pairs having strong 3D interactions, some of the pathogeneses have already been reported, such as PAX5 , a transcription factor crucial for B-cell commitment and maintenance, which typically fuses with KIAA1549L in childhood B-cell precursor ALL (BCP-ALL) 36 . In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene ( KMT2A ), specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), MLLT10, PDS5A, AFF4 and so on, are common fusion partners of KMT2A 37 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A 3D genome atlas of genetic variants and their pathological effects

Tang

2022

Preprint

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The spatial architecture of the genome can be categorized into distinct layers. Each layer plays a critical role in transcriptional regulation and/or genomic integrity. Alterations at any level of the 3D genome can lead to an unwanted cascade of molecular events, which may ultimately drive the manifestation of disease. However, a comprehensive atlas of the mutations and structural genetic defects that affect genome organization has yet to be compiled. Moreover, we lack a centralized resource for interpretating the pathological effects of such genetic mutations. Therefore, we curated from the literature all the pathological alterations from the chromosome level on down to single nucleotide polymorphisms (SNPs) in order to investigate these diverse genetic mutations. Using a two-phase scoring algorithm, 3DFunc, we scored the transcriptomic causality of all variants in the context of 3D genome architecture from 20 cancer and 15 normal tissues. Further, 3DFunc can identify pathological variant-gene pairs in non-oncological diseases. Finally, we constructed a web-based database, 3DGeOD (https://www.csuligroup.com/3DGeOD/home), to provide all the curated variants, genomic disruptions, as well as the scoring results derived from 3DFunc. In summary, our study constructed a 3D genome atlas of genetic variants and will serve as a valuable resource for mining the putative pathological effects of any genetic mutation.

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“…PAX5-related fusion proteins comprise two regions, the N-terminal PAX5 portion, which has a DNA-binding domain, and the C-terminal region, comprising one of various partner proteins (Nebral et al, 2009;Coyaud et al, 2010;Anderl et al, 2015;Fazio et al, 2015;Marincevic-Zuniga et al, 2016). In general, these fusions localize to the nucleus and bind to PAX5 target genes at their promotor regions (Fortschegger et al, 2014), acting as dominant-negative inhibitors of wild-type PAX5 and resulting in a block of differentiation of B lymphocytes (Fazio et al, 2008) .…”

Section: Discussionmentioning

confidence: 99%

Ph‐like acute lymphoblastic leukemia with a novel PAX5‐KIDINS220 fusion transcript

Sakamoto

Imamura

Kanayama

et al. 2016

Genes Chromosomes & Cancer

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Although "paired box 5" (PAX5)-related fusion genes are well documented in childhood B-cell precursor acute lymphoblastic leukemia (ALL), these types of fusion with the exception of PAX5-JAK2 are rarely seen in patients with gene expression profiles similar to those of BCR-ABL1 (Philadelphia)-positive ALL (Ph-like ALL). We report a novel fusion of the genes PAX5 and "kinase D-interacting substrate of 220 kDa" (KIDINS220, also known as ARMS) in a Ph-like ALL. As PAX5 is a master regulator of B-lymphocyte differentiation, PAX5 rearrangements induce a differentiation block in B lymphocytes. KIDINS220 is a mediator of multiple receptor signaling pathways, interacts with both T- and B-cell receptors, and is necessary for sustained extracellular signal-regulated kinase (ERK) signaling. Although functional studies are needed, the PAX5-KIDINS220 fusion protein might not only inhibit wild-type PAX5 function, but also promote sustained activation of the ERK signaling pathway through upregulation of KIDINS220. © 2016 Wiley Periodicals, Inc.

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PAX5-KIAA1549L: a novel fusion gene in a case of pediatric B-cell precursor acute lymphoblastic leukemia

Cited by 7 publications

References 37 publications

Genetic Influences on Evening Preference Overlap with Those for Bipolar Disorder in a Sample of Mexican Americans and American Indians

Genetic Influences on Evening Preference Overlap with Those for Bipolar Disorder in a Sample of Mexican Americans and American Indians

A 3D genome atlas of genetic variants and their pathological effects

Ph‐like acute lymphoblastic leukemia with a novel PAX5‐KIDINS220 fusion transcript

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