Candidate genes for expansion and transformation of hematopoietic stem cells by NUP98-HOX fusion genes - PubMed (original) (raw)

Candidate genes for expansion and transformation of hematopoietic stem cells by NUP98-HOX fusion genes

Lars Palmqvist et al. PLoS One. 2007.

Abstract

Background: Hox genes are implicated in hematopoietic stem cell (HSC) regulation as well as in leukemia development through translocation with the nucleoporin gene NUP98. Interestingly, an engineered NUP98-HOXA10 (NA10) fusion can induce a several hundred-fold expansion of HSCs in vitro and NA10 and the AML-associated fusion gene NUP98-HOXD13 (ND13) have a virtually indistinguishable ability to transform myeloid progenitor cells in vitro and to induce leukemia in collaboration with MEIS1 in vivo.

Methodology/principal findings: These findings provided a potentially powerful approach to identify key pathways mediating Hox-induced expansion and transformation of HSCs by identifying gene expression changes commonly induced by ND13 and NA10 but not by a NUP98-Hox fusion with a non-DNA binding homedomain mutation (N51S). The gene expression repertoire of purified murine bone marrow Sca-1+Lin- cells transduced with retroviral vectors encoding for these genes was established using the Affymetrix GeneChip MOE430A. Approximately seventy genes were differentially expressed in ND13 and NA10 cells that were significantly changed by both compared to the ND13(N51S) mutant. Intriguingly, several of these potential Hox target genes have been implicated in HSC expansion and self-renewal, including the tyrosine kinase receptor Flt3, the prion protein, Prnp, hepatic leukemia factor, Hlf and Jagged-2, Jag2. Consistent with these results, FLT3, HLF and JAG2 expression correlated with HOX A cluster gene expression in human leukemia samples.

Conclusions: In conclusion this study has identified several novel Hox downstream target genes and provides important new leads to key regulators of the expansion and transformation of hematopoietic stem cells by Hox.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Venn diagram of genes significantly activated (A) or repressed (B) in Sca1+, Lin- BM cells expressing the ND13, NA10 or ND13(N51S) mutant fusion genes compared to GFP control.

Figure 2

Figure 2. Annotation of differentially expressed genes.

Genes that were differentially expressed by both ND13 and NA10 but not the mutant ND13(N51S) mutant were classified according to involvement in different biological processes. Some genes are classified in more than one category resulting in the total number of genes indicated in the figures being greater than the total number of differentially expressed genes.

Figure 3

Figure 3. Correlation between HOXA7 and HOXA9 (A) and JAG2 and HLF (B) gene expression in human AML analyzed with TaqMan Low Density Array (TLDA).

Spearman rank correlation analysis was done on the log ratio values obtained from the TLDA assay and calculated with the 2−ΔΔCT method (n = 34).

Similar articles

Cited by

References

    1. Abramovich C, Humphries RK. Hox regulation of normal and leukemic hematopoietic stem cells. Curr Opin Hematol. 2005;12:210–216. - PubMed
    1. Grier DG, Thompson A, Kwasniewska A, McGonigle GJ, Halliday HL, et al. The pathophysiology of HOX genes and their role in cancer. J Pathol. 2005;205:154–171. - PubMed
    1. Slape C, Aplan PD. The role of NUP98 gene fusions in hematologic malignancy. Leuk Lymphoma. 2004;45:1341–1350. - PubMed
    1. Borrow J, Stanton VP, Jr, Andresen JM, Becher R, Behm FG, et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet. 1996;14:33–41. - PubMed
    1. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, et al. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia. Cancer Res. 1998;58:4269–4273. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources