NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice.
Here we describe hemopoietic chimeras serving as a mouse model for NUP98-HOXA9-induced leukemia, which reproduced several of the phenotypes observed in human disease. Mice transplanted with bone marrow cells expressing NUP98-HOXA9 through retroviral transduction acquire a myeloproliferative disease (MPD) and eventually succumb to acute myeloid leukemia (AML). The NUP98 portion of the fusion protein was shown to be responsible for transforming a clinically silent pre-leukemic phase observed for Hoxa9 into a chronic, stem cell-derived MPD. The co-expression of NUP98-HOXA9 and Meis1 accelerated the transformation of MPD to AML, identifying a genetic interaction previously observed for Hoxa9 and Meis1. Our findings demonstrate the presence of overlapping yet distinct molecular mechanisms for MPD versus AML, illustrating the complexity of leukemic transformation.
Kroon
E
E
Laboratory of Molecular Genetics of Hemopoietic Stem Cells, Clinical Research Institute of Montréal, Montréal, Québec, H2W 1R7, Canada.
Thorsteinsdottir
U
U
Mayotte
N
N
Nakamura
T
T
Sauvageau
G
G
D000818:Animals; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002678:Chimera; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007942:Leukemia, Experimental / Q000209:etiology* / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C400441:NUP98-HOXA9 fusion protein, human; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion