Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7

Benjamin J. Thompson, Vladimir Jankovic, Jie Gao, Silvia Buonamici, Alan Vest, Jennifer May Lee, Jiri Zavadil, Stephen D Nimer, Iannis Aifantis

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108 Scopus citations

Abstract

Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7-/- HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional "signature" that is associated with the quiescent, self-renewing HSC phenotype.

Original languageEnglish
Pages (from-to)1395-1408
Number of pages14
JournalJournal of Experimental Medicine
Volume205
Issue number6
DOIs
StatePublished - Jun 9 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Thompson, B. J., Jankovic, V., Gao, J., Buonamici, S., Vest, A., Lee, J. M., Zavadil, J., Nimer, S. D., & Aifantis, I. (2008). Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7. Journal of Experimental Medicine, 205(6), 1395-1408. https://doi.org/10.1084/jem.20080277