Delineating domains and functions of NUP98 contributing to the leukemogenic activity of NUP98-HOX fusions.
To determine the contribution of the common N-terminal truncation of NUP98 in NUP98-translocations resulting in acute myeloid leukemia, we have conducted a structure-function analysis of NUP98 in the context of NUP98-HOXA10HD, a novel, canonical NUP98-Hox fusion that significantly enhances the self-renewal capacity of hematopoietic stem cells and collaborates with Meis1 to induce AML in our mouse models. Our results identify that NUP98 functions by transcriptional activation likely by recruitment of CBP/p300 via its FG/GLFG repeats. In contrast, the functional interaction of NUP98 with Rae1 or the anaphase promoting complex appears non-essential for its role in NUP98-leukemogenic fusions.
Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.
Eric
E
Yung
Sanja
S
Sekulovic
Bob
B
Argiropoulos
Courteney K
CK
Lai
Malina
M
Leung
Tobias
T
Berg
Sarah
S
Vollett
Vicky Chi-Dan
VC
Chang
Adrian
A
Wan
Sandy
S
Wong
R Keith
RK
Humphries
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020449:Repetitive Sequences, Amino Acid; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D034521:Nuclear Matrix-Associated Proteins; D028861:Nuclear Pore Complex Proteins; D029543:Nucleocytoplasmic Transport Proteins; D015514:Oncogene Proteins, Fusion; C490521:Rae1 protein, mouse; C093350:nuclear pore complex protein 98; C092119:Hoxa10 protein, mouse; D050880:p300-CBP Transcription Factors