Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation

Jon C. Aster, Nick Bodnar, Lanwei Xu, Fredrick Karnell, John M. Milholland, Ivan Maillard, Gavin Histen, Yunsun Nam, Stephen C. Blacklow, Warren S. Pear

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: The functional interchangeability of mammalian Notch receptors (Notch1-4) in normal and pathophysiologic contexts such as cancer is unsettled. We used complementary in vivo, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival. Principal Findings: We find that the activated intracellular domains of Notch1-4 (ICN1-4) all support T cell development in mice and thymic organ culture. However, unlike ICN1-3, ICN4 fails to induce T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and is unable to rescue the growth of Notch1-dependent T-ALL cell lines. The ICN4 phenotype is mimicked by weak gain-of-function forms of Notch1, suggesting that it stems from a failure to transactivate one or more critical target genes above a necessary threshold. Experiments with chimeric receptors demonstrate that the Notch ankyrin repeat domains differ in their leukemogenic potential, and that this difference correlates with activation of Myc, a direct Notch target that has an important role in Notch-associated T-ALL. Conclusions/Significance: We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis.

Original languageEnglish (US)
Article numbere25645
JournalPLoS One
Volume6
Issue number10
DOIs
StatePublished - Oct 13 2011

Fingerprint

Ankyrin Repeat
ankyrins
T-cells
transcriptional activation
Transcriptional Activation
lymphocytic leukemia
T-lymphocytes
lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
T-Lymphocytes
Notch Receptors
receptors
Genes
organ culture
stems
Organ Culture Techniques
Cell growth
Growth
Cell culture
cell viability

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Aster, J. C., Bodnar, N., Xu, L., Karnell, F., Milholland, J. M., Maillard, I., ... Pear, W. S. (2011). Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. PLoS One, 6(10), [e25645]. https://doi.org/10.1371/journal.pone.0025645

Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. / Aster, Jon C.; Bodnar, Nick; Xu, Lanwei; Karnell, Fredrick; Milholland, John M.; Maillard, Ivan; Histen, Gavin; Nam, Yunsun; Blacklow, Stephen C.; Pear, Warren S.

In: PLoS One, Vol. 6, No. 10, e25645, 13.10.2011.

Research output: Contribution to journalArticle

Aster, JC, Bodnar, N, Xu, L, Karnell, F, Milholland, JM, Maillard, I, Histen, G, Nam, Y, Blacklow, SC & Pear, WS 2011, 'Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation', PLoS One, vol. 6, no. 10, e25645. https://doi.org/10.1371/journal.pone.0025645
Aster JC, Bodnar N, Xu L, Karnell F, Milholland JM, Maillard I et al. Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. PLoS One. 2011 Oct 13;6(10). e25645. https://doi.org/10.1371/journal.pone.0025645
Aster, Jon C. ; Bodnar, Nick ; Xu, Lanwei ; Karnell, Fredrick ; Milholland, John M. ; Maillard, Ivan ; Histen, Gavin ; Nam, Yunsun ; Blacklow, Stephen C. ; Pear, Warren S. / Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation. In: PLoS One. 2011 ; Vol. 6, No. 10.
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