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p210BCR/ABL-induced alteration of pre-mRNA splicing in primary human CD34+ hematopoietic progenitor cells

Leukemia volume 18, pages 727–733 (2004)Cite this article

Abstract

Chronic myelogenous leukemia (CML) is a malignancy of the human hematopoietic stem cell (HSC) caused by the p210BCR/ABL oncoprotein. Although alternative splicing of pre-mRNA is a critical determinant of a cell's protein repertoire, it has not been associated with CML pathogenesis. We identified a BCR/ABL-dependent increase in expression of multiple genes involved in pre-mRNA splicing (eg SRPK1, RNA Helicase II/Gu, and hnRNPA2/B1) by subtractive hybridization of cDNA from p210BCR/ABL-eGFP vs eGFP-transduced umbilical cord blood CD34+ cells. β1-integrin signaling is important to HSC maintenance and proliferation/differentiation, and is abnormal in CML. As an example of how changes in pre-mRNA processing might contribute to CML pathogenesis, we observed alternative splicing of a gene for a β1-integrin-responsive nonreceptor tyrosine kinase (PYK2), resulting in increased expression of full-length Pyk2 in BCR/ABL-containing cells. Treatment of p210BCR/ABL-positive cells with the Abl-specific tyrosine kinase inhibitor STI571 reverted PYK2 splicing to a configuration more consistent with normal cells, and correlated with decreased expression of BCR/ABL-induced proteins involved in pre-mRNA processing. Whether altered PYK2 splicing contributes to CML pathogenesis remains undetermined; however, we propose that generic changes in pre-mRNA splicing as a result of p210BCR/ABL kinase activity may contribute to CML pathogenesis.

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Acknowledgements

We thank Dr M Garcia-Blanco for valuable comments and Janet Peller, Brad Anderson, and members of the Stem Cell Lab for technical assistance. Additional thanks to Drs B Valdez, B Turner, I Dikic, and Novartis for reagents critical to these studies. This work was supported by grants from the National Institute of Health (RO1 HL-49930 and RO1 DK-53673), Leukemia and Lymphoma Society of America H6377-97; the Tulloch Family Foundation and the McKnight Foundation to CMV, and the Bone Marrow Transplant Research Fund and NCI-awarded Cancer Biology Training Grant (CA09138) to SJD.

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  1. S Salesse and S J Dylla: These authors contributed equally to this manuscript

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  1. Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA

    S Salesse, S J Dylla & C M Verfaillie

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Correspondence to C M Verfaillie.

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Salesse, S., Dylla, S. & Verfaillie, C. p210BCR/ABL-induced alteration of pre-mRNA splicing in primary human CD34+ hematopoietic progenitor cells. Leukemia 18, 727–733 (2004). https://doi.org/10.1038/sj.leu.2403310

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