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Acute Lymphoblastic Leukemia

CDK2 catalytic activity and loss of nuclear tethering of retinoblastoma protein in childhood acute lymphoblastic leukemia

Leukemia volume 19, pages 1783–1787 (2005)Cite this article

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. During cell cycle progression from the mid- to late G1 phase, mammalian cells traverse the restriction point, a transition from mitogen dependence to mitogen independence, regulated by retinoblastoma protein (Rb). Different cyclin-dependent kinases (CDKs) sequentially phosphorylate and inactivate Rb, which is associated by a change in Rb's nuclear affinity and activation of E2F transcription. Here, we show by in vitro kinase assays that ALL extracts contained CDK2 catalytic activity. When liberation of Rb from cell nuclei was tested by immune precipitation of differential cell extractions and Western blot analysis, little Rb was associated with the nuclear compartment. Together with the immunocytochemical analysis at a single cell level that Rb was phosphorylated at serine 612 and threonine 821, sites known to be phosphorylated by CDK2, the data indicated the presence of CDK2 catalytic activity and loss of Rb's nuclear affinity in ALL cells. We conclude that most ALL cells reside at or beyond the restriction point. This could explain the resistance of ALL cells to differentiation induction.

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Acknowledgements

We thank Regula Buergi, Anne-Marie Schmid and Christine Zala for technical assistance. This work was supported by grants from the Swiss National Science Foundation (#32-46838.96, #32-59005.99), the Foundation for Clinical and Experimental Cancer Research Bern, the Bernese Cancer League, and the Stammbach Foundation Basel, Switzerland.

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Authors and Affiliations

  1. Department of Clinical Research, University of Bern, Bern, Switzerland

    N M R Schmitz, K Leibundgut & A Hirt

  2. Department of Pediatrics, University Children's Hospital Inselspital Bern, University of Bern, Bern, Switzerland

    N M R Schmitz, K Leibundgut & A Hirt

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  1. N M R Schmitz
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  2. K Leibundgut
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  3. A Hirt
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Correspondence to N M R Schmitz.

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

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Schmitz, N., Leibundgut, K. & Hirt, A. CDK2 catalytic activity and loss of nuclear tethering of retinoblastoma protein in childhood acute lymphoblastic leukemia. Leukemia 19, 1783–1787 (2005). https://doi.org/10.1038/sj.leu.2403900

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