Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease

Anupriya Agarwal, Thomas G.P. Bumm, Amie S. Corbin, Thomas O'Hare, Marc Loriaux, Jonathan Van Dyke, Stephanie G. Willis, Jutta Deininger, Keiichi I. Nakayama, Brian J. Druker, Michael W. Deininger

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52 Citations (Scopus)

Abstract

BCR-ABL is proposed to impair cell-cycle control by disabling p27, a tumor suppressor that inhibits cyclin-dependent kinases. We show that in cell lines p27 expression is inversely correlated with expression of SKP2, the F-box protein of SCF SKP2 (SKP1/Cul1/F-box), the E3 ubiquitin ligase that promotes proteasomal degradation of p27. Inhibition of BCR-ABL kinase causes G 1 arrest, downregulation of SKP2, and accumulation of p27. Ectopic expression of wild-type SKP2, but not a mutant unable to recognize p27, partially rescues cell-cycle progression. A similar regulation pattern is seen in cell lines transformed by FLT3-ITD, JAK2 V617F, and TEL-PDGFRβ, suggesting that the SKP2/p27 conduit may be a universal target for leukemogenic tyrosine kinases. Mice that received transplants of BCR-ABL-infected SKP2 -/- marrow developed a myeloproliferative syndrome but survival was significantly prolonged compared with recipients of BCR-ABL-expressing SKP2 +/+ marrow. SKP2 -/- leukemic cells demonstrated higher levels of nuclear p27 than SKP2 +/+ counterparts, suggesting that the attenuation of leukemogenesis depends on increased p27 expression. Our data identify SKP2 as a crucial mediator of BCR-ABL-induced leukemogenesis and provide the first in vivo evidence that SKP2 promotes oncogenesis. Hence, stabilization of p27 by inhibiting its recognition by SCF SKP2 may be therapeutically useful.

Original languageEnglish
Pages (from-to)1960-1970
Number of pages11
JournalBlood
Volume112
Issue number5
DOIs
Publication statusPublished - Sep 1 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Agarwal, A., Bumm, T. G. P., Corbin, A. S., O'Hare, T., Loriaux, M., Van Dyke, J., Willis, S. G., Deininger, J., Nakayama, K. I., Druker, B. J., & Deininger, M. W. (2008). Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease. Blood, 112(5), 1960-1970. https://doi.org/10.1182/blood-2007-09-113860