Molecular analysis of an unstable genomic region at chromosome band 11q23 reveals a disruption of the gene encoding the α2 subunit of platelet-activating factor acetylhydrolase (Pafah1a2) in human lymphoma

Lecointe, Nathalie; Meerabux, Joanne; Ebihara, Mitsuru; Hill, Alexander S.; Young, Bryan D.

doi:10.1038/sj.onc.1202645

Cited by 19 publications

(6 citation statements)

References 43 publications

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“…2004). As mentioned earlier, the α2 expression is thought to be up‐regulated by chromosomal translocation in certain human lymphomas (Lecointe et al . 1999).…”

Section: Discussionmentioning

confidence: 81%

“…Centrosome amplification is known to frequently occur in human cancer (Kawamura et al 2004). As mentioned earlier, the α2 expression is thought to be up-regulated by chromosomal translocation in certain human lymphomas (Lecointe et al 1999). Our finding that over-expression of α2 in the cell induces centrosome amplification suggests that this phenomenon is a major cause of cellular transformation occurring in the lymphoma cases mentioned above.…”

Section: Discussionmentioning

confidence: 89%

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Type I platelet‐activating factor acetylhydrolase catalytic subunits over‐expression induces pleiomorphic nuclei and centrosome amplification

Yamaguchi¹,

Koizumi²,

Aoki³

et al. 2007

Genes to Cells

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LIS1, a causative gene product for type I lissencephaly, binds to and regulates the dynein motor and the centrosome. LIS1 also forms a complex with the catalytic subunits α1 and α2 of type I platelet‐activating factor acetylhydrolase [PAF‐AH (I)]. However, the cellular function of the catalytic subunits remains unknown. In this study, we showed that over‐expression of the catalytic subunits, especially α2, in cultured cells induced dramatic phenotypical changes including nuclear shape change, centrosomal amplification and microtubule disorganization. We examined if these effects were due to the catalytic activity and/or binding of α2 to LIS1. Substitution of a single amino acid Glu39 of murine α1 and α2 by Asp (α2‐E39D) did not affect catalytic activity but completely abolished LIS1 binding. Over‐expression of either α2‐E39D or the catalytically inactive α2‐S48C revealed that α2‐E39D, but not α2‐S48C, lost its ability to induce above‐mentioned phenotypic changes. Biochemical analyses showed that LIS1 present in the precipitate fraction of murine brain homogenates could be translocated to the soluble fraction by α2, but not by α2‐E39D. These results suggest that over‐expression of the PAF‐AH (I) catalytic subunits induces centrosomal amplification and microtubule disorganization by disturbing intracellular localization of LIS1.

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“…2004). As mentioned earlier, the α2 expression is thought to be up‐regulated by chromosomal translocation in certain human lymphomas (Lecointe et al . 1999).…”

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 89%

Type I platelet‐activating factor acetylhydrolase catalytic subunits over‐expression induces pleiomorphic nuclei and centrosome amplification

Yamaguchi¹,

Koizumi²,

Aoki³

et al. 2007

Genes to Cells

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“…The PAFAH1B2 gene has been previously recognized as target of IGH locus translocations in 2 lymphoma cases. 37 Such IGH translocation leads typically to oncogene activation and it is therefore consequent to suggest PAFAH1B2 (previously named PAFAH1A2) as an oncogene in lymphomagenesis. Furthermore, it has been found to interact at protein level with ZFP36L1, 38 another partner of IGH translocations described in chronic lymphocytic leukemia 39,40 and the target of hypermutation in DLBCL.…”

Section: Discussionmentioning

confidence: 99%

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma

Salaverría

Martín-Guerrero

Wagener

et al. 2014

Blood

189

133

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Key Points• A subset of lymphomas with gene expression and pathological characteristics of Burkitt lymphomas but absence of MYC translocation does exist.• These lymphomas carry chr 11q proximal gains and telomeric losses, suggesting co-deregulation of oncogenes and tumor suppressor genes.The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by highlevel amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation

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“…In the B‐cell leukemia line Karpas 231, t(3;11)(q27;q23) resulted in the fusion of B‐cell‐specific transcription coactivator POU2AF1, on 11q23, with BCL6 (Galieque Zouitina et al, 1996). Other genes mapping to 11q23 that are of pathogenetic significance in lymphoproliferative disorders include RCK , PLZF , and PAFAH1B2 (Akao et al, 1991; Meerabux et al, 1996; Lecointe et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Translocation t(X;11)(q13;q23) in B‐cell chronic lymphocytic leukemia disrupts two novel genes

Kalla

Nentwich

Schlotter

et al. 2004

Genes Chromosomes & Cancer

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Deletion of chromosome region 11q22-q23 defines a subgroup of patients with B-cell chronic lymphocytic leukemia (B-CLL) characterized by poor survival. Although the tumor-suppressor gene ATM in the consensus deletion region was found to be biallelically inactivated in about one third of B-CLL cases, in the majority of those who have this deletion, inactivation of the remaining ATM allele was not observed. To identify a second disease-associated gene, we investigated two B-CLL cases with translocation breakpoints in the critical 11q23 deletion region. In one case, a t(X;11)(q13;q23) was cloned and two novel genes were isolated. The breakpoint on 11q23 affected the ARHGAP20 gene, which encodes a protein predicted to be involved in the regulation of Rho family GTPases. The breakpoint on Xq13 occurred in BRWD3, which codes for a putative novel transcription factor. The rearrangement of ARHGAP20 and BRWD3 did not result in fusion transcripts, but it disrupted both genes. Mutation analysis of 28 B-CLL samples with monoallelic deletions and two B-CLL samples with 11q23 translocations detected no deleterious mutation in the remaining copy of ARHGAP20. Quantitative expression analysis in 22 B-CLLs revealed significant up-regulation of ARHGAP20 in CLL B cells, whereas BRWD3 was slightly down-regulated. Thus, deregulation of ARHGAP20 by altered gene expression or by gene disruption (but not point mutation) might be a general molecular mechanism of B-CLL leukemogenesis.

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Molecular analysis of an unstable genomic region at chromosome band 11q23 reveals a disruption of the gene encoding the α2 subunit of platelet-activating factor acetylhydrolase (Pafah1a2) in human lymphoma

Cited by 19 publications

References 43 publications

Type I platelet‐activating factor acetylhydrolase catalytic subunits over‐expression induces pleiomorphic nuclei and centrosome amplification

Type I platelet‐activating factor acetylhydrolase catalytic subunits over‐expression induces pleiomorphic nuclei and centrosome amplification

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma

Translocation t(X;11)(q13;q23) in B‐cell chronic lymphocytic leukemia disrupts two novel genes

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