NUP98 gene fusions in hematologic malignancies

Lam, Du; Aplan, Peter D.

doi:10.1038/sj.leu.2402269

Cited by 96 publications

(84 citation statements)

References 73 publications

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“…Consistent with a role in modulating transcription, gene expression profiling of NUP98-HOXA9-expressing myeloid cells revealed a significant increase in the number of genes upregulated compared to HoxA9-expressing myeloid cells (Ghannam et al, 2004). It has also been proposed that the transforming potential of NUP98-HOX fusions may reflect their increased protein stability (Calvo et al, 2002;Chung et al, 2006) or their ability to alter nucleocytoplasmic transport of mRNA and/or protein (Lam and Aplan, 2001). …”

Section: Deficiencies Of Hox Regulators Demonstrate a Role For Hox Gementioning

confidence: 79%

Hox genes in hematopoiesis and leukemogenesis

2007

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Section: Deficiencies Of Hox Regulators Demonstrate a Role For Hox Gementioning

confidence: 79%

Hox genes in hematopoiesis and leukemogenesis

2007

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“…These include results of experiments testing the effect of forced overexpression of HOXA9 [37] and preliminary data using engineered NUP98-HOX fusion genes [28], identified because of their implied role in leukemogenesis [38]. All NUP98-HOX fusions reported to date include the N-terminus of NUP98, which contains a region of multiple phenylalanine-glycine repeats that may act as a transcriptional co-activator through binding to CBP/p300 [39] and the C-terminus of the HOX gene product, including the intact homeodomain and a variable portion of the flanking amino acids [38]. The engineered NUP98 fusions we had previously studied included both HOXB4, a member of the Ant-class group, as well as HOXA10, which belongs to a different Abd-B class of HOX genes; and both of these were found to stimulate a marked expansion in vitro of multipotent spleen colonyforming cells.…”

Section: Discussionmentioning

confidence: 99%

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

Ohta

Sekulovic

Bakovic

et al. 2007

Experimental Hematology

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Objective-Strategies to expand hematopoietic stem cells (HSCs) ex vivo are of key interest. The objective of this study was to resolve if ability of HOXB4, previously documented to induce a significant expansion of HSCs in culture, may extend to other HOX genes and also to further analyze the HOX sequence requirements to achieve this effect.Methods-To investigate the ability of Nucleoporin98-Homeobox fusion genes to stimulate HSC self-renewal, we evaluated their presence in 10-to 20-day cultures of transduced mouse bone marrow cells. Stem cell recovery was measured by limiting-dilution assay for long-term competitive repopulating cells (CRU Assay).Results-These experiments revealed remarkable expansions of Nucleoporin98-Homeoboxtransduced HSCs (1000-fold to 10,000-fold over input) in contrast to the expected decline of HSCs in control cultures. Nevertheless, the Nucleoporin98-Homeobox-expanded HSCs displayed no proliferative senescence and retained normal lympho-myeloid differentiation activity and a controlled pool size in vivo. Analysis of proviral integration patterns showed the cells regenerated in vivo were highly polyclonal, indicating they had derived from a large proportion of the initially targeted HSCs. Importantly, these effects were preserved when all HOX sequences flanking the homeodomain were removed, thus defining the homeodomain as a key and independent element in the fusion.Conclusion-These findings create new possibilities for investigating HSCs biochemically and genetically and for achieving clinically significant expansion of human HSCs.The self-renewal function of hematopoietic stem cells (HSCs) is essential to their ability to sustain lifelong hematopoiesis and to regenerate the hematopoietic system after myeloablative treatments. This property is the basis of an increasing range of applications of HSC transplants to treat various malignant and genetic disorders [1,2]. Further improvements in the safety and therapeutic utility of HSC transplants can be readily envisaged if robust methods for largescale ex vivo expansion of HSCs were available. For example, the low absolute numbers of HSCs in most cord blood samples [3] [4] restrict the clinical utility of these products. A method for significantly expanding HSCs could not only address these insufficiencies but also broaden the exploitation of reduced conditioning regimens and associated therapeutic benefits.One approach that has allowed some HSC expansion in vitro to be achieved has focused on the identification of optimized combinations and concentrations of externally acting growth factors and related molecules [5][6][7][8][9][10][11][12]. A complementary approach has been to identify intrinsic regulators such as transcription factors [13] and key mediators of signaling pathways [14,15] that can be manipulated to activate or promote HSC self-renewal divisions. A striking example of the latter strategy is the use of retrovirally engineered overexpression of the homeobox transcription factor HOXB4 to stimulate expansions of HSC numb...

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“…1 More than one half of the partners are homeobox genes, with 7 belonging to paralogs 9, 11, and 13 of the abdominal-B cluster of HOX. Moreover, at least 2 such fusions, NUP98-HOXA9 and NUP98-HOXD13, were shown to have direct, potent effects on hematopoiesis and to induce a lethal MPD/AML in mice.…”

Section: Discussionmentioning

confidence: 99%

“…1 To date, 15 distinct fusion partners have been identified in NUP98 translocations. The most frequently observed fusion partners for NUP98 belong to the homeobox family of transcription factors and include HOXA9, 2,3 HOXD13, 4 HOXD11, 5 HOXA11, 6 HOXA13, 7,8 HOXC11, 9 and HOXC13 10 as well as the nonclustered homeobox gene PMX1.…”

Section: Introductionmentioning

confidence: 99%

NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation

Gurevich

Aplan

Humphries

2004

Blood

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Chromosomal rearrangements of the 11p15 locus have been identified in hematopoietic malignancies, resulting in translocations involving the N-terminal portion of the nucleoporin gene NUP98. Fifteen different fusion partner genes have been identified for NUP98, and more than one half of these are homeobox transcription factors. By contrast, the NUP98 fusion partner in t(11;20) is Topoisomerase I (TOP1), a catalytic enzyme recognized for its key role in relaxing supercoiled DNA. We now show that retrovirally engineered expression of NUP98-TOP1 in murine bone marrow confers a potent in vitro growth advantage and a block in differentiation in hematopoietic precursors, evidenced by a competitive growth advantage in liquid culture, increased replating efficient of colony-forming cells (CFCs), and a marked increase in spleen colonyforming cell output. Moreover, in a murine bone marrow transplantation model, NUP98-TOP1 expression led to a lethal, transplantable leukemia characterized by extremely high white cell counts, splenomegaly, and mild anemia. Strikingly, a mutation to a TOP1 site to inactivate the isomerase activity essentially left unaltered the growth-promoting and leukemogenic effects of NUP98-TOP1. These findings, together with similar biologic effects reported for NUP98-HOX fusions, suggest unexpected, overlapping functions of NUP98 fusion genes, perhaps related to common DNA binding properties. IntroductionA heterogenous group of hematopoietic malignancies has been described that are characterized by chromosomal translocations that create fusion genes involving the N-terminal portion of the nucleoporin gene, NUP98, on chromosome 11p15. 1 To date, 15 distinct fusion partners have been identified in NUP98 translocations. The most frequently observed fusion partners for NUP98 belong to the homeobox family of transcription factors and include HOXA9, 2,3 HOXD13, 4 HOXD11, 5 HOXA11, 6 HOXA13, 7,8 HOXC11,9 and HOXC13 10 as well as the nonclustered homeobox gene PMX1. 11 Recent studies in murine model systems have clearly demonstrated that both NUP98-HOXA9 and NUP98-HOXD13 play a causal and overt role in the pathogenesis of leukemia. 12,13 Furthermore, the disease onset can be greatly accelerated in these models by coexpression of the NUP98-HOX fusion gene and the HOX co-factor Meis1. These reports are consistent with the observations that HOX genes play key roles in the regulation of hematopoiesis and that overexpression of select HOX genes (eg, HOXA10, 14 HOXB3 15 ) lead to leukemia.In addition to the HOX genes, 7 "variant" partner genes that are associated with a wide range of biologic functions have been identified in fusion with NUP98 in hematopoietic malignancies. These include DDX10, 16,17 RAP1GDS1,18,19 Topoisomerase I, 20 LEDGF, 21 NSD1, 22 NSD3, 23 and Adducin 3. 24 These NUP98 fusion partner genes are diverse in function and, in contrast to the HOX fusion partners, are not known to have a specific or unique function in hematopoiesis.An intriguing example of one such non-HOX partner is Topoisomerase I (...

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NUP98 gene fusions in hematologic malignancies

Cited by 96 publications

References 73 publications

Hox genes in hematopoiesis and leukemogenesis

Hox genes in hematopoiesis and leukemogenesis

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation

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