Transplantable cell lines generated with NUP98-Hox fusion genes undergo leukemic progression by Meis1 independent of its binding to DNA.
Hox genes have been identified in chromosomal translocations involving the nucleoporin gene NUP98. Though the resulting chimeric proteins directly participate in the development of leukemia, the long latency and monoclonal nature of the disease support the requirement for secondary mutation(s), such as those leading to overexpression of Meis1. Models to identify such events and to study leukemic progression are rare and labor intensive. Herein, we took advantage of the strong transforming potential of NUP98-HOXD13 or NUP98-HOXA10 to establish preleukemic myeloid lines from bone marrow cells that faithfully replicate the first step of Hox-induced leukemogenesis. These lines contain early granulomonocytic progenitors with extensive in vitro self-renewal capacity, short-term myeloid repopulating activity and low propensity for spontaneous leukemic conversion. We exploit such lines to show that Meis1 efficiently induces their leukemic progression and demonstrate a high frequency of preleukemic cells in the cultures. Furthermore, we document that the leukemogenic potential of Meis1 is independent of its direct binding to DNA and likely reflects its ability to increase the repopulating capacity of the preleukemic cells by increasing their self-renewal/proliferative capacity. The availability of lines with repopulating potential and capacity for leukemic conversion should open new avenues for understanding progression of Hox-mediated acute myeloid leukemia.
Pineault
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Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Abramovich
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Humphries
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RK
D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors
D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C470262:NUP98-HOXC13 fusion protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C490289:VSX2 protein, human