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Chronic Myeloproliferative Neoplasias

Role of BCR-ABL-Y177-mediated p27kip1 phosphorylation and cytoplasmic localization in enhanced proliferation of chronic myeloid leukemia progenitors

Leukemia volume 24, pages 779–787 (2010)Cite this article

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Abstract

In chronic myelogenous leukemia (CML), hematopoietic stem cell transformation leads to increased proliferation of malignant myeloid progenitors. The cyclin-dependent kinase inhibitor p27kip1 (p27) is a critical negative regulator of hematopoietic progenitor proliferation and pool size that is deregulated in BCR-ABL expressing cell lines. However, cell-context specific regulation of p27 in primary human CML progenitors and its contribution to CML progenitor expansion remain unclear. Here, we investigated p27 regulation and function in (1) CD34+ cells from CML patients and (2) human CD34+ cells ectopically expressing the BCR-ABL gene following retrovirus transduction. We found that p27 levels are increased in CML CD34+ cells related to a BCR-ABL-dependent increase in p27 protein translation. However, p27 was relocated to the cytoplasm in CML progenitors and nuclear p27 levels were reduced, allowing increased cell cycling and expansion in culture. Cytoplasmic relocation of p27 in CML progenitors was related to signaling through BCR-ABL Y177, activation of the AKT kinase and phosphorylation of p27 on Thr-157 (T157). Expression of a mutant p27 that cannot be phosphorylated on T157 significantly inhibited CML progenitor proliferation. These studies show the importance of BCR-ABL-Y177-AKT-mediated p27 phosphorylation in altered p27 localization and enhanced proliferation and expansion of primary CML progenitors.

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Acknowledgements

This work was supported by NIH grant R01 CA95684, R01 HL77847 (RB) and General Clinical Research Center Grant #5M01. We acknowledge the excellent technical support of the City of Hope Analytical Cytometry Core and the Light Microscopy Digital Imaging Core. We thank Allen Lin for assistance with obtaining samples and StemCyte for their generous gift of cord blood samples. We thank Dr J Slingerland, University of Miami, for the p27 and p27 T157A constructs.

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  1. Division of Hematopoietic Stem Cell and Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA

    S Chu, T McDonald & R Bhatia

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Correspondence to R Bhatia.

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Author contributions: SC designed and performed research, analyzed data and wrote manuscript; TM performed experiments and reviewed manuscript; RB designed study, analyzed data and wrote manuscript.

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Chu, S., McDonald, T. & Bhatia, R. Role of BCR-ABL-Y177-mediated p27kip1 phosphorylation and cytoplasmic localization in enhanced proliferation of chronic myeloid leukemia progenitors. Leukemia 24, 779–787 (2010). https://doi.org/10.1038/leu.2010.24

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