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G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia

Oncogene volume 24, pages 5561–5575 (2005)Cite this article

Abstract

The HOX11/TLX1 homeobox gene is aberrantly expressed in a subset of T-cell acute lymphoblastic leukemia (T-ALL). Here, we employed oligonucleotide microarrays to compare the expression profiles of the K3P and Sil leukemic cell lines originating from patients with HOX11+ T-ALL to that of Jurkat cells, which originated from a distinct subtype of T-ALL (TAL1+). To distinguish potential HOX11 target genes from those characteristic of the stage of HOX11 leukemic arrest, we also performed gene expression analysis on Jurkat cells, genetically engineered to express exogenous HOX11. The resulting HOX11 gene expression signature, which was validated for representative signaling pathways by transient transfection of reporter constructs, was characterized by elevated expression of transcriptional programs involved in cell proliferation, including those regulated by E2F, c-Myc and cAMP response element-binding protein. We subsequently showed that ectopic HOX11 expression resulted in hyperphosphorylation of the retinoblastoma protein (Rb), which correlated with inhibition of the major Rb serine/threonine phosphatase PP1. HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade. These results suggest that transcriptional deregulation of G1/S growth-control genes, mediated in large part through blockade of PP1/PP2A phosphatase activity, plays an important role in HOX11 pathobiology.

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Acknowledgements

We gratefully acknowledge Vladimir Kuznetsov for statistical analysis support and Timothy McCaffrey for advice on GeneSpring software. We also thank Wen-mei Yu for technical assistance during part of this work and help with data presentation, Joseph Molete and Teresa Hawley for providing NIH3T3/iHOX11 cells, and Ali Ramezani for the gift of the β-catenin lentiviral vector. This work was supported in part by National Institutes of Health grants R01HL65519, R01HL66305 and R24RR16209.

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    Irene Riz & Robert G Hawley

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Correspondence to Robert G Hawley.

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Riz, I., Hawley, R. G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia. Oncogene 24, 5561–5575 (2005). https://doi.org/10.1038/sj.onc.1208727

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