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Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARα

Oncogene volume 23, pages 665–678 (2004)Cite this article

Abstract

Acute promyelocytic leukemia (APL) is characterized by the accumulation of abnormal promyelocytes in the bone marrow (BM), and by the presence of a reciprocal chromosomal translocation involving retinoic acid receptor alpha (RARα). To date, five RARα partner genes have been identified in APL. NuMA-RARα was identified in a pediatric case of APL carrying a translocation t(11;17)(q13;q21). Using a construct containing the NuMA-RARα fusion gene driven by the human cathepsin G promoter (hCG-NuMA-RARα), two transgenic mouse lines were generated. Transgenic mice were observed to have a genetic myeloproliferation (increased granulopoiesis in BM) at an early age, and rapidly developed a myeloproliferative disease-like myeloid leukemia. This leukemia was morphologically and immunophenotypically indistinguishable from human APL, with a penetrance of 100%. The phenotype of transgenic mice was consistent with a blockade of neutrophil differentiation. NuMA-RARα is therefore sufficient for disease development in this APL model.

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Abbreviations

APL:

acute promyelocytic leukemia

ATRA:

all trans-retinoic acid

BM:

bone marrow

CFU:

colony-forming unit

LTMC:

long-term marrow culture

My/Ly:

myeloid/lymphoid

MPD:

myeloproliferative disorder

NPM :

nucleophosmin

NuMA :

nuclear mitotic apparatus

PB:

peripheral blood

PML :

promyelocytic leukemia

PLZF :

promyelocytic leukemia zinc-finger

RARα :

retinoic acid receptor alpha

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Acknowledgements

We thank Dr S Arora for reading of the manuscript. This work was supported by funding from the National Cancer Institute of Canada (Grant #13087 to SK-R) and the National Institutes of Health (Grant #s R01 CA74031, R01 CA71692, and U01 CA84292 to PPP). MAS is an Ontario Graduate Scholar. We also gratefully acknowledge the disability accommodations funding provided through the University of Toronto, Office of Accessibility Services.

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Mahadeo A Sukhai & Suzanne Kamel-Reid

  2. Department of Cellular and Molecular Biology, the Ontario Cancer Institute/University Health Network, Toronto, Ontario, Canada

    Mahadeo A Sukhai, Yali Xuan, Tong Zhang, Patricia P Reis, Karina Dubé, Denis J Bailey & Suzanne Kamel-Reid

  3. Molecular Biology Program and Department of Pathology, Molecular and Developmental Biology Lab, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY, USA

    Xuemei Wu, Eduardo M Rego, Mantu Bhaumik, Richard A Wells & Pier Paolo Pandolfi

  4. Department of Pathology, The Ontario Cancer Institute/University Health Network, Toronto, Ontario, Canada

    Denis J Bailey & Suzanne Kamel-Reid

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Suzanne Kamel-Reid

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  1. Mahadeo A Sukhai
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  2. Xuemei Wu
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Correspondence to Suzanne Kamel-Reid.

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Sukhai, M., Wu, X., Xuan, Y. et al. Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARα. Oncogene 23, 665–678 (2004). https://doi.org/10.1038/sj.onc.1207073

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