Notch ankyrin repeat domain variation influences leukemogenesis and Myc transactivation.
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.


RESULTS
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
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.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America. jaster@rics.bwh.harvard.edu
Jon C
JC
Aster
Nick
N
Bodnar
Lanwei
L
Xu
Fredrick
F
Karnell
John M
JM
Milholland
Ivan
I
Maillard
Gavin
G
Histen
Yunsun
Y
Nam
Stephen C
SC
Blacklow
Warren S
WS
Pear
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017089:Ankyrin Repeat; D055592:Biophysical Phenomena / Q000187:drug effects; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D014644:Genetic Variation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009924:Organ Culture Techniques; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D060168:Thymocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D014161:Transduction, Genetic
D010455:Peptides; D011480:Protease Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases