Oncogenic interaction between BCR-ABL and NUP98-HOXA9 demonstrated by the use of an in vitro purging culture system.
Chronic myelogenous leukemia (CML) is a clonal stem cell disease caused by the BCR-ABL oncoprotein and is characterized, in its early phase, by excessive accumulation of mature myeloid cells, which eventually leads to acute leukemia. The genetic events involved in CML's progression to acute leukemia remain largely unknown. Recent studies have detected the presence of the NUP98-HOXA9 fusion oncogene in acute leukemia derived from CML patients, which suggests that these 2 oncoproteins may interact and influence CML disease progression. Using in vitro purging of BCR-ABL-transduced mouse bone marrow cells, we can now report that recipients of bone marrow cells engineered to coexpress BCR-ABL with NUP98-HOXA9 develop acute leukemia within 7 to 10 days after transplantation. However, no disease is detected for more than 2 months in mice receiving bone marrow cells expressing either BCR-ABL or NUP98-HOXA9. We also provide evidence of high levels of HOXA9 expressed in leukemic blasts from acute-phase CML patients and that it interacts significantly on a genetic level with BCR-ABL in our in vivo CML model. Together, these studies support a causative, as opposed to a consequential, role for NUP98-HOXA9 (and possibly HOXA9) in CML disease progression.
Mayotte
Nadine
N
Laboratory of Molecular Genetics of Stem Cells, Clinical Research Institute of Montreal, QC, Canada.
Roy
Denis-Claude
DC
Yao
Jing
J
Kroon
Evert
E
Sauvageau
Guy
G
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation; D018929:Cell Culture Techniques / Q000379:methods; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D014161:Transduction, Genetic
D018398:Homeodomain Proteins; C400441:NUP98-HOXA9 fusion protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D016044:Fusion Proteins, bcr-abl