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Hematopoietic immortalizing function of the NKL-subclass homeobox gene TLX1.

ABSTRACT: Translocations resulting in ectopic expression of the TLX1 homeobox gene (previously known as HOX11) are recurrent events in human T-cell acute lymphoblastic leukemia (T-ALL). Transduction of primary murine hematopoietic stem/progenitor cells with retroviral vectors expressing TLX1 readily yields immortalized hematopoietic progenitor cell lines. Understanding the processes involved in TLX1-mediated cellular immortalization should yield insights into the growth and differentiation pathways altered by TLX1 during the development of T-ALL. In recent clinical gene therapy trials, hematopoietic clonal dominance or T-ALL-like diseases have occurred as a direct consequence of insertional activation of the EVI1, PRDM16 or LMO2 proto-oncogenes by the retroviral vectors used to deliver the therapeutic genes. Additionally, the generation of murine hematopoietic progenitor cell lines due to retroviral integrations into Evi1 or Prdm16 has also been recently reported. Here, we determined by linker-mediated nested polymerase chain reaction the integration sites in eight TLX1-immortalized hematopoietic cell lines. Notably, no common integration site was observed among the cell lines. Moreover, no insertions into the Evi1 or Prdm16 genes were identified although insertion near Lmo2 was observed in one instance. However, neither Lmo2 nor any of the other genes examined surrounding the integration sites showed differential vector-influenced expression compared to the cell lines lacking such insertions. While we cannot exclude the possibility that insertional side effects transiently provided a selective growth/survival advantage to the hematopoietic progenitor populations, our results unequivocally rule out insertions into Evi1 and Prdm16 as being integral to the TLX1-initiated immortalization process.

SUBMITTER: Zweier-Renn LA

PROVIDER: S-EPMC2795049 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Hematopoietic immortalizing function of the NKL-subclass homeobox gene TLX1.

Zweier-Renn Lynnsey A LA Hawley Teresa S TS Burkett Sandra S Ramezani Ali A Riz Irene I Adler Rima L RL Hickstein Dennis D DD Hawley Robert G RG

Genes, chromosomes & cancer 20100201 2

Translocations resulting in ectopic expression of the TLX1 homeobox gene (previously known as HOX11) are recurrent events in human T-cell acute lymphoblastic leukemia (T-ALL). Transduction of primary murine hematopoietic stem/progenitor cells with retroviral vectors expressing TLX1 readily yields immortalized hematopoietic progenitor cell lines. Understanding the processes involved in TLX1-mediated cellular immortalization should yield insights into the growth and differentiation pathways altere ...[more]

PMID: 19862821

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Project description:Recently, we have documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in early hematopoiesis and in lymphopoiesis, which spotlights genes deregulated in lymphoid malignancies. Here, we enlarge this map to include normal NKL homeobox gene expressions in myelopoiesis by analyzing public expression profiling data and primary samples from developing and mature myeloid cells. We thus uncovered differential activities of six NKL homeobox genes, namely DLX2, HHEX, HLX, HMX1, NKX3-1 and VENTX. We further examined public expression profiling data of 251 acute myeloid leukemia (AML) and 183 myelodysplastic syndrome (MDS) patients, thereby identifying 24 deregulated genes. These results revealed frequent deregulation of NKL homeobox genes in myeloid malignancies. For detailed analysis we focused on NKL homeobox gene NANOG, which acts as a stem cell factor and is correspondingly expressed alone in hematopoietic progenitor cells. We detected aberrant expression of NANOG in a small subset of AML patients and in AML cell line NOMO-1, which served as a model. Karyotyping and genomic profiling discounted rearrangements of the NANOG locus at 12p13. But gene expression analyses of AML patients and AML cell lines after knockdown and overexpression of NANOG revealed regulators and target genes. Accordingly, NKL homeobox genes HHEX, DLX5 and DLX6, stem cell factors STAT3 and TET2, and the NOTCH-pathway were located upstream of NANOG while NKL homeobox genes HLX and VENTX, transcription factors KLF4 and MYB, and anti-apoptosis-factor MIR17HG represented target genes. In conclusion, we have extended the NKL-code to the myeloid lineage and thus identified several NKL homeobox genes deregulated in AML and MDS. These data indicate a common oncogenic role of NKL homeobox genes in both lymphoid and myeloid malignancies. For misexpressed NANOG we identified an aberrant regulatory network, which contributes to the understanding of the oncogenic activity of NKL homeobox genes.

Dataset Information

Hematopoietic immortalizing function of the NKL-subclass homeobox gene TLX1.

Publications

Hematopoietic immortalizing function of the NKL-subclass homeobox gene TLX1.

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