Title | Enforced expression of NUP98-HOXA9 in human CD34(+) cells enhances stem cell proliferation. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Chung KY, Morrone G, Schuringa JJacob, Plasilova M, Shieh J-H, Zhang Y, Zhou P, Moore MAS |
Journal | Cancer Res |
Volume | 66 |
Issue | 24 |
Pagination | 11781-91 |
Date Published | 2006 Dec 15 |
ISSN | 0008-5472 |
Keywords | Antigens, CD, Antigens, CD34, Cell Division, Cell Line, Chromosome Mapping, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 7, Cloning, Molecular, Colony-Forming Units Assay, Fetal Blood, Gene Fusion, Genetic Vectors, Homeodomain Proteins, Humans, Mutant Chimeric Proteins, Nuclear Pore Complex Proteins, Oligonucleotide Array Sequence Analysis, Retroviridae, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells, Translocation, Genetic, Umbilical Cord |
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 alpha. 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. |
DOI | 10.1158/0008-5472.CAN-06-0706 |
Alternate Journal | Cancer Res |
PubMed ID | 17178874 |
Grant List | CA092210 / CA / NCI NIH HHS / United States CA118085 / CA / NCI NIH HHS / United States |
Related Faculty:
Pengbo Zhou, Ph.D.