Enforced expression of NUP98-HOXA9 in human CD34+ cells enhances stem cell proliferation Journal Article
| Authors: | Chung, K. Y.; Morrone, G.; Schuringa, J. J.; Plasilova, M.; Shieh, J.H.; Zhang, Y.; Zhou, P.; Moore, M. A. S. |
| Article Title: | Enforced expression of NUP98-HOXA9 in human CD34+ cells enhances stem cell proliferation |
| Abstract: | The t(7;11)(p15;p15) translocation, observed in acute myelogenous leukemia and myelodysplastic syndrome, generates a chimeric gene where the 5′ portion of the sequence encoding the human nucleoporin NUP98 protein is fused to the 3′ region of HOXA9. Here, we show that retroviral-mediated enforced expression of the NUP98-HOXA9 fusion protein in cord blood-derived CD34 + cells confers a proliferative advantage in both cytokine-stimulated suspension cultures and stromal coculture. This advantage is reflected in the selective expansion of hematopoietic stem cells as measured in vitro by cobblestone area-forming cell assays and in vivo by competitive repopulation of nonobese diabetic/severe combined immunodeficient mice. NUP98-HOXA9 expression inhibited erythroid progenitor differentiation and delayed neutrophil maturation in transduced progenitors but strongly enhanced their serial replating efficiency. Analysis of the transcriptosome of transduced cells revealed up-regulation of several homeobox genes of the A and B cluster as well as of Meis1 and Pim-1 and down-modulation of globin genes and of CAAT/enhancer binding protein α. The latter gene, when coexpressed with NUP98-HOXA9, reversed the enhanced proliferation of transduced CD34+ cells. Unlike HOXA9, the NUP98-HOXA9 fusion was protected from ubiquitination mediated by Cullin-4A and subsequent proteasome-dependent degradation. The resulting protein stabilization may contribute to the leukemogenic activity of the fusion protein. ©2006 American Association for Cancer Research. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; cell proliferation; cell division; cell maturation; erythroid precursor cell; protein degradation; cell line; cell differentiation; homeodomain proteins; in vitro study; genetic vectors; stem cell; cloning, molecular; cytokine; fetal blood; ubiquitination; hybrid protein; neutrophil; cell culture; reverse transcriptase polymerase chain reaction; oligonucleotide array sequence analysis; gene fusion; globin; stem cells; umbilical cord blood; translocation, genetic; down regulation; upregulation; hematopoietic stem cell; antigens, cd; homeodomain protein; immune deficiency; stroma cell; nonobese diabetic mouse; colony-forming units assay; antigens, cd34; chromosomes, human, pair 11; cd34 selection; retrovirus; retroviridae; chromosome mapping; nucleoporin 98; nuclear pore complex proteins; mutant chimeric proteins; umbilical cord; chromosomes, human, pair 7; protein hoxa 9 |
| Journal Title: | Cancer Research |
| Volume: | 66 |
| Issue: | 24 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-12-15 |
| Start Page: | 11781 |
| End Page: | 11791 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-06-0706 |
| PUBMED: | 17178874 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus" |
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