Cargando…

Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9

NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-H...

Descripción completa

Detalles Bibliográficos
Autores principales: Yassin, Enas R., Sarma, Nayan J., Abdul-Nabi, Anmaar M., Dombrowski, James, Han, Ye, Takeda, Akiko, Yaseen, Nabeel R.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725295/
https://www.ncbi.nlm.nih.gov/pubmed/19696924
http://dx.doi.org/10.1371/journal.pone.0006719
_version_ 1782170505916186624
author Yassin, Enas R.
Sarma, Nayan J.
Abdul-Nabi, Anmaar M.
Dombrowski, James
Han, Ye
Takeda, Akiko
Yaseen, Nabeel R.
author_facet Yassin, Enas R.
Sarma, Nayan J.
Abdul-Nabi, Anmaar M.
Dombrowski, James
Han, Ye
Takeda, Akiko
Yaseen, Nabeel R.
author_sort Yassin, Enas R.
collection PubMed
description NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-HOXA9 can regulate transcription without binding to DNA. In order to determine the relative contributions of the NUP98 and HOXA9 portions to the transforming ability of NUP98-HOXA9, the effects of NUP98-HOXA9 on primary human CD34+ cells were dissected and compared to those of wild-type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferation of primary human hematopoietic cells. The ability of NUP98-HOXA9 to disrupt the differentiation of primary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation required both the NUP98 moiety and an intact homeodomain. Using oligonucleotide microarrays in primary human CD34+ cells, a group of genes was identified whose dysregulation by NUP98-HOXA9 is attributable primarily to the NUP98 portion. These include RAP1A, HEY1, and PTGS2 (COX-2). Their functions may reflect the contribution of the NUP98 moiety of NUP98-HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcription and cell transformation are mediated by at least two distinct mechanisms: one that involves promoter binding through the homeodomain with direct transcriptional activation, and another that depends predominantly on the NUP98 moiety and does not involve direct DNA binding.
format Text
id pubmed-2725295
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-27252952009-08-21 Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9 Yassin, Enas R. Sarma, Nayan J. Abdul-Nabi, Anmaar M. Dombrowski, James Han, Ye Takeda, Akiko Yaseen, Nabeel R. PLoS One Research Article NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-HOXA9 can regulate transcription without binding to DNA. In order to determine the relative contributions of the NUP98 and HOXA9 portions to the transforming ability of NUP98-HOXA9, the effects of NUP98-HOXA9 on primary human CD34+ cells were dissected and compared to those of wild-type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferation of primary human hematopoietic cells. The ability of NUP98-HOXA9 to disrupt the differentiation of primary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation required both the NUP98 moiety and an intact homeodomain. Using oligonucleotide microarrays in primary human CD34+ cells, a group of genes was identified whose dysregulation by NUP98-HOXA9 is attributable primarily to the NUP98 portion. These include RAP1A, HEY1, and PTGS2 (COX-2). Their functions may reflect the contribution of the NUP98 moiety of NUP98-HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcription and cell transformation are mediated by at least two distinct mechanisms: one that involves promoter binding through the homeodomain with direct transcriptional activation, and another that depends predominantly on the NUP98 moiety and does not involve direct DNA binding. Public Library of Science 2009-08-21 /pmc/articles/PMC2725295/ /pubmed/19696924 http://dx.doi.org/10.1371/journal.pone.0006719 Text en Yassin et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Yassin, Enas R.
Sarma, Nayan J.
Abdul-Nabi, Anmaar M.
Dombrowski, James
Han, Ye
Takeda, Akiko
Yaseen, Nabeel R.
Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9
title Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9
title_full Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9
title_fullStr Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9
title_full_unstemmed Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9
title_short Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9
title_sort dissection of the transformation of primary human hematopoietic cells by the oncogene nup98-hoxa9
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725295/
https://www.ncbi.nlm.nih.gov/pubmed/19696924
http://dx.doi.org/10.1371/journal.pone.0006719
work_keys_str_mv AT yassinenasr dissectionofthetransformationofprimaryhumanhematopoieticcellsbytheoncogenenup98hoxa9
AT sarmanayanj dissectionofthetransformationofprimaryhumanhematopoieticcellsbytheoncogenenup98hoxa9
AT abdulnabianmaarm dissectionofthetransformationofprimaryhumanhematopoieticcellsbytheoncogenenup98hoxa9
AT dombrowskijames dissectionofthetransformationofprimaryhumanhematopoieticcellsbytheoncogenenup98hoxa9
AT hanye dissectionofthetransformationofprimaryhumanhematopoieticcellsbytheoncogenenup98hoxa9
AT takedaakiko dissectionofthetransformationofprimaryhumanhematopoieticcellsbytheoncogenenup98hoxa9
AT yaseennabeelr dissectionofthetransformationofprimaryhumanhematopoieticcellsbytheoncogenenup98hoxa9