Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia

Nebral, Karin; Denk, Dagmar; Attarbaschi, Andishe; König, Margit; Mann, Georg; Haas, Oskar A.; Strehl, Sabine

doi:10.1038/leu.2008.306

Cited by 186 publications

(143 citation statements)

References 55 publications

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“…The t(9;14)(pl3;q32) chromosomal translocation involving PAX5 and the potent Emu enhancer of the IgH gene was recently reported in cases of B-cell lymphoma leading to elevated PAX5 expression. Moreover, the rearrangements of PAX5 gene were also found in patients with B-cell acute lymphoblastic leukemia such as PAX5-ETV6 (TEL), PAX5-EVI3, PAX5-ELN, PAX5-FOXP1, PAX5-ZNF521 and PAX5-C20orf112 (Kawamata et al, 2008;Nebral et al, 2009). In addition, the decreased PAX5 gene expression was reported in one third of B-cell ALL patients (Mullighan et al, 2007).…”

Section: Introductionmentioning

confidence: 97%

The reduced and altered activities of PAX5 are linked to the protein–protein interaction motif (coiled-coil domain) of the PAX5–PML fusion protein in t(9;15)-associated acute lymphocytic leukemia

Qiu

Chu

et al. 2010

Oncogene

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The paired box domain of PAX5 was reported to fuse with the sequence of promyelocytic leukemia (PML) to produce PAX5-PML chimeric protein in two patients with B-cell acute lymphoblastic leukemia. In the present studies, we found, by gel shift assays, that PAX5-PML bound to a panel of PAX5-consensus sequence acts as a homodimer with reduction of its DNA-binding affinities in comparison with wild-type PAX5. In transient transfection assays using 293T and HeLa cells, and retrovirus transduction of murine hematopoietic stem/progenitor cells together with quantitative real-time polymerase chain reaction analysis, PAX5-PML inhibited wild-type PAX5 target gene transcriptional activity. Studies comparing PAX5-PML with PAX5-PML(DCC) demonstrated that the coiled-coil (CC) protein interaction domain located within the PML moiety was required for PAX5-PML homodimer complex formation and partial transcriptional repression of genes controlled by PAX5. Fluorescent microscopic examination of transiently expressed YFP-tagged proteins in HeLa and 293T cells demonstrated that YFP-PAX5-PML and YFP-PAX5-PML(DCC) exhibited a diffuse granular pattern within the nucleus, similar to PAX5 but not PML. By fluorescent recovery after photobleach (FRAP), we have shown that PAX5-PML fusion protein has reduced intranuclear mobility compared with wild-type PAX5. Furthermore, the dimerization domain (CC) of PML was responsible for the reduced intranuclear mobility of PAX5-PML. These results indicate that the CC domain of PAX5-PML is important for each of the known activities of PAX5-PML fusion proteins.

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Section: Introductionmentioning

confidence: 97%

The reduced and altered activities of PAX5 are linked to the protein–protein interaction motif (coiled-coil domain) of the PAX5–PML fusion protein in t(9;15)-associated acute lymphocytic leukemia

Qiu

Chu

et al. 2010

Oncogene

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“…Subsequent studies have identified additional PAX5 fusions in ALL, involving multiple partner genes including ASXL1, AUTS2, BRD1, C20orf112, DACH1, ELN, HIPK1, JAK2, KIF3B, LOC392027, PML, POM121 and SLCO1B3. 47,[63][64][65][66] The overall frequency of PAX5 translocations appears low (B2.6% B-ALL cases), 66 although studies comprehensively examining PAX5 translocation in large B-ALL cohorts are awaited. Genomic resequencing of PAX5 in the St Jude study described above also identified 16 missense, insertion/deletion, splice site and frameshift mutations that clustered in the key DNA-binding and transactivating domains of PAX5.…”

Section: Mutations Of Genes Regulating B-lymphoid Development In Allmentioning

confidence: 99%

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

2009

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Until recently, our understanding of the genetic factors contributing to the pathogenesis of acute lymphoblastic leukemia (ALL) has relied on the detection of gross chromosomal alterations and mutational analysis of individual genes. Although these approaches have identified many important abnormalities, they have been unable to identify the full repertoire of genetic alterations in ALL. The advent of highresolution, microarray-based techniques to identify DNA copy number alterations and loss-of-heterozygosity in a genomewide fashion has enabled the identification of multiple novel genetic alterations targeting key cellular pathways, including lymphoid differentiation, cell cycle, tumor suppression, apoptosis and drug responsiveness. Recent studies have extended these approaches to examine the biologic basis of high-risk ALL and treatment relapse. As these techniques continue to evolve and are integrated with genome-wide epigenetic and transcriptomic data, we will obtain a comprehensive understanding of the genetic and epigenetic alterations in ALL, and ultimately will be able to translate these findings into the development of novel therapeutic approaches directed against rational therapeutic targets. Here, we review recent data obtained from genome-wide profiling studies in ALL, and discuss potential avenues for future investigation.

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“…2, and the structural statistics are given in Table 2. The structural coordinates of human BRPF2-PHD1, both free and fused to unH3 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), have been deposited into the Protein Data Bank with accession codes 2KU3 and 2L43, respectively.…”

Section: Brpf2-phd1 Preferentially Binds To Histone H3k4me0-mentioning

confidence: 99%

Recognition of Unmodified Histone H3 by the First PHD Finger of Bromodomain-PHD Finger Protein 2 Provides Insights into the Regulation of Histone Acetyltransferases Monocytic Leukemic Zinc-finger Protein (MOZ) and MOZ-related factor (MORF)

Jin

Zhang

et al. 2011

Journal of Biological Chemistry

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MOZ (monocytic leukemic zinc-finger protein) and MORF (MOZ-related factor) are histone acetyltransferases important for HOX gene expression as well as embryo and postnatal development. They form complexes with other regulatory subunits through the scaffold proteins BRPF1/2/3 (bromodomain-PHD (plant homeodomain) finger proteins 1, 2, or 3). BRPF proteins have multiple domains, including two PHD fingers, for potential interactions with histones. Here we show that the first PHD finger of BRPF2 specifically recognizes the N-terminal tail of unmodified histone H3 (unH3) and report the solution structures of this PHD finger both free and in complex with the unH3 peptide. Structural analysis revealed that the unH3 peptide forms a third antiparallel ␤-strand that pairs with the PHD1 two-stranded antiparallel ␤-sheet. The binding specificity was determined primarily through the recognition of arginine 2 and lysine 4 of the unH3 by conserved aspartic acids of PHD1 and of threonine 6 of the unH3 by a conserved asparagine. Isothermal titration calorimetry and NMR assays showed that post-translational modifications such as H3R2me2as, H3T3ph, H3K4me, H3K4ac, and H3T6ph antagonized the interaction between histone H3 and PHD1. Furthermore, histone binding by PHD1 was important for BRPF2 to localize to the HOXA9 locus in vivo. PHD1 is highly conserved in yeast NuA3 and other histone acetyltransferase complexes, so the results reported here also shed light on the function and regulation of these complexes.Histone acetyltransferases (HATs) 3 are enzymes that catalyze the transfer of an acetyl group from acetyl-CoA to the ⑀-amino groups of lysine on histones, which results in important regulatory effects in chromatin structure and assembly as well as gene expression. HATs are highly diverse and generally form multiprotein complexes. Different HAT complexes are composed of various unique subunits, and the combination of these subunits contributes to the unique features of each HAT complex (1).MOZ (monocytic leukemic zinc-finger protein) and MORF (MOZ-related factor), a pair of large HATs of the MYST (Moz, Ybf2/Sas3, Sas2, Tip60) family, are important for hematopoiesis, skeletogenesis, neurogenesis, and other developmental processes, and they also have been implicated in leukemogenic and other tumorigenic progressions (2). A recent study in mice embryos reported that MOZ is required for normal levels of spatially correct Hox gene expression and for correct body segment identity. MOZ is specifically required for the H3K9 acetylation of active Hox gene loci (3). MOZ is also required for the maintenance of hematopoietic stem cells and plays a role in the differentiation of erythroid and myeloid cells (4). By contrast, MORF is required for the maintenance of undifferentiated neuronal progenitors and for adult neural stem cell self-renewal and neuronal differentiation (5). MOZ and MORF genes are often translocated in acute myeloid leukemia cells, producing either fusion proteins with CBP (cAMP-response elementbinding protein (CREB)-bind...

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Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia

Cited by 186 publications

References 55 publications

The reduced and altered activities of PAX5 are linked to the protein–protein interaction motif (coiled-coil domain) of the PAX5–PML fusion protein in t(9;15)-associated acute lymphocytic leukemia

The reduced and altered activities of PAX5 are linked to the protein–protein interaction motif (coiled-coil domain) of the PAX5–PML fusion protein in t(9;15)-associated acute lymphocytic leukemia

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

Recognition of Unmodified Histone H3 by the First PHD Finger of Bromodomain-PHD Finger Protein 2 Provides Insights into the Regulation of Histone Acetyltransferases Monocytic Leukemic Zinc-finger Protein (MOZ) and MOZ-related factor (MORF)

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