NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogénétique Hématologique

Romana, Serge; Radford‐Weiss, Isabelle; Abdelali, Raouf Ben; Schluth, Caroline; Petit, Arnaud; Dastugue, Nicole; Talmant, Pascaline; Bilhou-Nabéra, Chrystèle; Mugneret, Francine; Lafage‐Pochitaloff, Marina; Mozziconacci, Marie‐Joëlle; Andrieu, Jean‐Marie; Laı̈, Jean-Luc; Terré, Christine; Rack, Katrina; Cornillet‐Lefèbvre, Pascale; Luquet, Isabelle; Nadal, Nathalie; Nguyen‐Khac, Florence; Pérot, Christine; Akker, Jacqueline van den; Fert‐Ferrer, Sandra; Cabrol, C; Charrin, C; Tigaud, Isabelle; Poirel, Hélène; Vekemans, Michel; Bernard, Olivier A.; Berger, Roland

doi:10.1038/sj.leu.2404130

Cited by 122 publications

(115 citation statements)

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“…We also identified a deletion endpoint located at a common translocation breakpoint in the NUP98 gene on chromosome 11p15.5, although there were no cytogenetic translocations detected in this patient. Cryptic translocations between NUP98 and NSD1 on chromosome 5q35.3 have been described in AML and can be missed by cytogenetics (16,17). Therefore, we screened this sample for evidence of a translocation involving NUP98 and NSD1.…”

Section: Identification Of Translocations and Genementioning

confidence: 99%

Acquired copy number alterations in adult acute myeloid leukemia genomes

Walter

Payton²,

Ries³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

227

176

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Cytogenetic analysis of acute myeloid leukemia (AML) cells has accelerated the identification of genes important for AML pathogenesis. To complement cytogenetic studies and to identify genes altered in AML genomes, we performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using 1.85 million feature SNP arrays. Acquired copy number alterations (CNAs) were confirmed using an ultra-dense array comparative genomic hybridization platform. A total of 201 somatic CNAs were found in the 86 AML genomes (mean, 2.34 CNAs per genome), with French-AmericanBritish system M6 and M7 genomes containing the most changes (10 -29 CNAs per genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, whereas 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several CNA regions were recurrent. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes; 6 of 8 UPD calls occurred in samples with a normal karyotype. Collectively, 34 of 86 AML genomes (40%) contained alterations not found with cytogenetics, and 98% of these regions contained genes. Of 86 genomes, 43 (50%) had no CNA or UPD at this level of resolution. In this study of 86 adult AML genomes, the use of an unbiased high-resolution genomic screen identified many genes not previously implicated in AML that may be relevant for pathogenesis, along with many known oncogenes and tumor suppressor genes. AML ͉ array CGH ͉ genomics ͉ SNP arrayA cute myeloid leukemia (AML) is a heterogeneous group of diseases currently classified by abnormalities in bone marrow morphology, karyotype, acquired gene mutations, and alterations in gene expression (1-3). Although the identification of specific gene mutations has resulted in improved treatments and outcomes for some AML patients (4), enormous clinical heterogeneity exists and may reflect the presence of as-yet undetected initiating and cooperating mutations. Therefore, the discovery of somatic mutations in the genomes of AML patients with normal and abnormal karyotypes will advance our understanding of the genetics underlying AML and should lead to more specific therapies and better patient classification schemes.The discovery of previously uncharacterized genes mutated in acute lymphoblastic leukemia (ALL) was recently reported using SNP array technology for DNA copy number analysis (5). SNP array platforms can detect genomic amplifications, deletions, SNP loss of heterozygosity (LOH), and regions of uniparental disomy (UPD) (copy-neutral LOH events) in cancer cells. Early studies using SNP arrays and array comparative genomic hybridization (CGH) platforms have suggested that both copy number alterations (CNAs) and UPD are common in AML genomes (6-12). However, these studies used low-resolution arrays, often used reference DNA that was not obtained from the same patient's n...

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Section: Identification Of Translocations and Genementioning

confidence: 99%

Acquired copy number alterations in adult acute myeloid leukemia genomes

Walter

Payton²,

Ries³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

227

176

View full text Add to dashboard Cite

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“…The most frequently observed NUP98 fusion partners belong to the homeobox gene family, including mostly clustered HOX genes and two non-clustered HOX genes, paired related homeobox 1 and 2 (PMX1 and PMX2) (Slape and Aplan, 2004;Romana et al, 2006). The involvement of these latter two genes in leukemia is intriguing, as in contrast to clustered Hox genes, neither gene has been previously implicated in normal hematopoiesis or leukemogenesis.…”

Section: Introductionmentioning

confidence: 94%

“…The nucleoporin gene NUP98 on chromosome 11p15 is involved in chromosomal rearrangements with at least 20 different partners (Slape and Aplan, 2004;Nakamura, 2005;Romana et al, 2006;Jankovic et al, 2008). NUP98 translocations have been described in de novo acute and chronic leukemias, as well as therapyrelated myelodysplastic syndrome and therapy-related acute myeloid leukemia (AML).…”

Section: Introductionmentioning

confidence: 99%

Leukemogenic properties of NUP98-PMX1 are linked to NUP98 and homeodomain sequence functions but not to binding properties of PMX1 to serum response factor

et al. 2008

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PMX1 is a member of a non-clustered homeobox gene family, not normally expressed in hematopoietic cells, and first identified for its role in enhancing the binding of the serum response factor (SRF) to the serum responsive element (SRE). PMX1 has never been linked to leukemia on its own, raising the possibility of unique mechanisms underlying the oncogenicity of NUP98-PMX1. To elucidate the leukemogenic potential of NUP98-PMX1, we compared the effects of PMX1 and NUP98-PMX1 and, through strategic mutations, the involvement of the SRE in NUP98-PMX1-mediated leukemia. NUP98-PMX1, but not PMX1, had potent ability to impair differentiation, promote proliferation of myeloid progenitors, induce lethal myeloproliferative disease and to activate a number of genes previously linked to leukemic stem cells. Similar to NUP98-HOX fusions, the transforming potential of NUP98-PMX1 required the NUP98 portion and DNA-binding capability of the PMX1 homeodomain and collaborated with Meis1 to induce more rapid onset myeloproliferative-like myeloid leukemia. The transforming activity of NUP98-PMX1 was independent of its ability to interact with SRF. These findings provide novel evidence of the contributory role of the NUP98 sequence in conferring leukemogenic properties on a partner gene and point to common leukemogenic pathways for NUP98-PMX1 and NUP98-clustered HOX fusions.

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“…9 We earlier reported the involvement of NUP98 in t(X;11)(q28;p15) in a 73-year-old woman with therapy-related acute myeloblastic leukemia (AML) with M4 subtype. 1 Fluorescence in situ hybridization experiments performed on metaphasic chromosome of the blast cells permitted the mapping of the translocation breakpoint on Xq28 in which only the HMGB3 gene had the correct transcription orientation (telomere to centromere) that would allow an in-frame fusion to NUP98 (assuming a simple translocation event). Reverse transcriptase-PCR using primers located within NUP98 and HMGB3 exons showed the presence of NUP98-HMGB3 fusion transcript from patient's material and not from control complementary DNA (cDNA) (Figure 1a).…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…1 Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J et al NUP98 is a promiscuous gene involved in chromosomal aberrations with more than 20 different partner genes in a variety of human hematological malignancies. 1,2 These rearrangements all lead to the expression of hybrid proteins that start with the amino-terminal moiety of NUP98.…”

Section: Conflict Of Interestmentioning

confidence: 99%