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Regulation of Hoxb2 by APL-associated PLZF protein

Oncogene volume 22, pages 3685–3697 (2003)Cite this article

Abstract

The PLZF gene is translocated in a subset of all-trans-retinoic acid resistant acute promyelocytic leukaemia (APL) cases, encodes a DNA binding transcription factor and is expressed highly in haematopoietic progenitor cells as well-developing central nervous system (CNS). The spatially restricted and temporally dynamic pattern of PLZF expression in the developing CNS suggested that it might play a role in the circuitry regulating hindbrain segmentation. We have now identified a PLZF binding site (PLZF-RE) in an enhancer region of Hoxb2 that itself is required for directing high-level expression in rhombomers 3 and 5 of the developing hindbrain. The wild-type r3/r5 enhancer linked to a heterologous promoter was responsive to regulation by PLZF, and this activity was lost in variants containing a mutated PLZF-RE. Compared with the wild-type protein, the binding of the APL-associated reciprocal RARα–PLZF fusion to PLZF-RE was much stronger, suggesting that the N-terminal PLZF sequences missing from the fusion may play a role in the regulation of DNA binding. Consistent with this, the N-terminal POZ domain was required for cooperative binding of PLZF to a multimerized PLZF-RE. In the context of the r3/r5 enhancer, the PLZF-RE cooperated for PLZF binding with an additional A/T-rich motif positioned downstream of the PLZF-RE. This A/T motif was previously shown to be essential for the regulation of Hoxb2 expression in r3 and r5 in cooperation with another Krüppel-like zinc finger protein Krox 20. The presence of both the PLZF-RE and the A/T-rich motif was required for a maximal effect of PLZF on a heterologous promoter and was essential in vivo to direct the expression of a lacZ reporter in the chick neural tube. Hence, both PLZF and Krox20 cooperate with a common A/T motif in mediating in vivo activity of the Hoxb2 enhancer. Our findings indicate that Hoxb2 is a direct target for regulation by PLZF in the developing CNS and suggest that deregulation of Hox gene expression may contribute to APL pathogenesis.

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Acknowledgements

We are grateful to Kevin Petrie, Jon D Licht and Helen Ball for comments and discussions. This work was supported by a studentship from the Medical Research Council of Great Britain (SI), a programme grant from the Leukaemia Research Fund of Great Britain and the National Institutes of Health Grant CA59936 (AZ) and core support from the Medical Research Council and Stowers Institute for Medical Research to RK.

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Authors and Affiliations

  1. Leukaemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London, SW3 6JB, UK

    Sarah Ivins, Fabien Guidez, Louise Howell & Arthur Zelent

  2. Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, 64110, MO, USA

    Kieran Pemberton & Robb Krumlauf

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  1. Sarah Ivins
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Correspondence to Arthur Zelent.

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Ivins, S., Pemberton, K., Guidez, F. et al. Regulation of Hoxb2 by APL-associated PLZF protein. Oncogene 22, 3685–3697 (2003). https://doi.org/10.1038/sj.onc.1206328

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