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Bcr-Abl-mediated suppression of normal hematopoiesis in leukemia

Oncogene volume 24, pages 1–11 (2005)Cite this article

Abstract

A variety of experimental evidence including findings in various mouse models indicates that the BCR-ABL oncogene is the cause of chronic myeloid leukemia (CML). Since normal hematopoietic cells in marrow and spleen are replaced with proliferating leukemic blasts, we determined whether this is an active process mediated by the leukemia cells. The lipocalin 24p3 was reported to be secreted by mouse hematopoietic cells deprived of IL-3, resulting in apoptosis induction in a variety of hematopoietic cells including bone marrow cells. Here, we show that BCR-ABL+ mouse hematopoietic cells induced persistent expression and secretion of 24p3. Importantly, BCR-ABL+ hematopoietic cells were resistant to the apoptotic effects of 24p3. The expression of the Bcr-Abl oncoprotein and its tyrosine kinase were required for induction of 24p3 expression. Co-culture studies showed that BCR-ABL+ cells induced apoptosis in BCR-ABL negative cells. Antisense 24p3/siRNA expression reduced the level of 24p3 protein in both BCR-ABL+ cells and in conditioned medium (CM) obtained from these cells. CM from BCR-ABL+ cells expressing antisense 24p3/siRNA had reduced apoptotic activity for target cells; 24p3 antibody also reduced the apoptotic activity of the CM. Leukemic mice induced by BCR-ABL+ cells expressing either antisense 24p3 or 24p3 siRNA had increased levels of normal hematopoiesis and reduced invasion of leukemia cells in marrow and spleen tissues. These findings indicate that suppression of normal hematopoiesis in BCR-ABL-induced leukemia is an active process involving secretion of the cell death-inducing factor 24p3 by mouse leukemia cells, raising the possibility that similar factors are involved in BCR-ABL+ CML.

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Acknowledgements

We thank Dr Merit Nielson-Hamilton (Iowa State University) for providing purified antibody against murine 24p3, and Dr Michael Green of the University of Massachusetts for supplying the 24p3 plasmid. We also thank Dr Roland Strong (Fred Hutchinson Cancer Center, Seattle) for supplying bacterially purified 24p3. We also thank Dr Shi Ke of the Department of Experimental Diagnostic Imaging at the MD Anderson Cancer Center for assistance in statistical analyses of the data. Affinity-purified antibody to 24p3 for apoptosis blocking experiments was a gift of Dr Sin-Tak CHU and Dr Yee-Hsiung Chen at the Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC. We also thank Yan Wang, MD and Liya Zhang, MS for excellent technical assistance. This research was supported in part by NIH Grants CA49639, CA16672 and from Funds from Richard Hendrick Marrow Foundation.

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Author notes

  1. Shanhai Xie

    Present address: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Hui Lin, Tong Sun, Xiaoyang Ling, Shanhai Xie & Ralph Arlinghaus

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Giuseppe Monaco & John Belmont

  3. Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Clifton Stephens

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  1. Hui Lin
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Correspondence to Ralph Arlinghaus.

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The authors declare they have no competing financial interest.

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

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Lin, H., Monaco, G., Sun, T. et al. Bcr-Abl-mediated suppression of normal hematopoiesis in leukemia. Oncogene 24, 1–11 (2005). https://doi.org/10.1038/sj.onc.1208500

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