NUP98 dysregulation in myeloid leukemogenesis Conference Paper
| Authors: | Moore, M. A. S.; Chung, K. Y.; Plasilova, M.; Schuringa, J. J.; Shieh, J.H.; Zhou, P.; Morrone, G. |
| Title: | NUP98 dysregulation in myeloid leukemogenesis |
| Conference Title: | 6th Biennial International Symposium and Workshop on Hematopoietic Stem Cells |
| Abstract: | Nucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia-associated chromosomal translocations. NUP98-HOXA9 is associated with the t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML),myelodysplastic syndrome, and blastic crisis of chronic myeloid leukemia. Expression of NUP98-HOXA9 in murine bone marrow resulted in a myeloproliferative disease progressing to AML by 7-8 months. Transduction of NUP98 fusion genes into human CD34+ cells confers a proliferative advantage in long-term cytokine-stimulated and stromal cocultures and in NOD-SCID engrafted mice, associated with a five- to eight-fold increase in hematopoietic stem cells. NUP98-HOXA9 expression inhibited erythroid andmyeloid differentiation but enhanced serial progenitor replating. NUP98-HOXA9 upregulated a number of homeobox genes of the A and B cluster as well as MEIS1 and Pim-1, and downmodulated globin genes and C/EBPα. The HOXA9 component of the NUP98-HOXA9 fusion proteinwas protected from cullin-4A-mediated ubiquitination and subsequent proteasome-dependent degradation. In NUP98-HOX-transduced CD34+ cells and cells from AML patients with t(7;11)(p15;p15) NUP98 was no longer associated with the nuclear pore complex but formed intranuclear aggregation bodies. Analysis of NUP98 allelic expression in AML and myelodysplastic syndrome showed loss of heterozygosity observed in 29% of the former and 8% of the latter. This was associated with poor prognosis. © 2007 New York Academy of Sciences. |
| Keywords: | immunohistochemistry; leukemia; unclassified drug; acute granulocytic leukemia; genetics; myeloproliferative disorder; review; nonhuman; conference paper; analysis; binding affinity; mouse; animal; metabolism; mouse mutant; animals; mice; allele; mus; cd34 antigen; enzyme inhibition; gene expression; alleles; cell differentiation; mice, scid; physiology; genetic transduction; stem cell; gene expression regulation; tumor suppressor gene; gene expression regulation, neoplastic; biosynthesis; myelodysplastic syndrome; ubiquitination; hybrid protein; microarray analysis; gene disruption; leukemogenesis; gene fusion; murinae; stem cells; chromosomal instability; chromosome translocation; upregulation; immunostimulation; cell nucleus; bone marrow cell; hematopoietic stem cell; heterozygosity loss; homeodomain protein; loss of heterozygosity; cyclin d1; mice, inbred nod; nonobese diabetic mouse; antigens, cd34; chromosome 11; chromosomes, human, pair 11; cd34 selection; gene location; myelodysplastic syndromes; cullin; downstream processing; chromosome 7; nucleoporin 98; nuclear pore complex proteins; transcription factor runx1; myeloid leukemia; protein p300; nucleoporin; homeobox; chromosome 11p; homeobox genes; ornithine decarboxylase; chromosomes, human, pair 7; leukemia, myelocytic, acute; cyclic amp responsive element binding protein binding protein; hoxa9; nup98 protein, human; myeloid leukemogenesis |
| Journal Title | Annals of the New York Academy of Sciences |
| Volume: | 1106 |
| Conference Dates: | 2006 Sept 14-16 |
| Conference Location: | Tübingen, Germany |
| ISBN: | 0077-8923 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2007-06-01 |
| Start Page: | 114 |
| End Page: | 142 |
| Language: | English |
| DOI: | 10.1196/annals.1392.019 |
| PUBMED: | 17442773 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Chapter in "Hematopoietic Stem Cells VI" -- "Cited By (since 1996): 28" - "Export Date: 17 November 2011" - "CODEN: ANYAA" - "Source: Scopus" |
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