title: Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells.
abstract: The polycomb group (PcG) proteins, particularly Bmi1, have an essential role in maintaining the self-renewing capacity of leukemic stem cells (LSCs). Although one of their major targets in LSCs is known to be the Ink4a/Arf tumor suppressor gene locus, the role of PcG proteins in the leukemic reprogramming of target cells into LSCs is not well characterized. In this study, Bmi1(-/-) granulocyte/macrophage progenitors (GMPs) were transformed with the leukemic fusion gene MLL-AF9. Although Bmi1 was not essential to the immortalization of GMPs in vitro, Bmi1(-/-) cells showed enhanced differentiation and retained less LSCs. A number of genes were derepressed in the absence of Bmi1 including potential tumor suppressor genes. Transplantation assays demonstrated that Bmi1 was indispensable for the development of leukemia in vivo and deletion of both the Ink4a and Arf genes only partially restored the leukemogenic capacity of Bmi1(-/-) LSCs. Of note, the complementation of immortalized Bmi1(-/-)Ink4a-Arf(-/-) GMPs with Bmi1 failed to restore the expression of the majority of deregulated genes and leukemogenic activity in vivo. These findings indicate that Bmi1 is essential for the faithful reprogramming of myeloid progenitors into LSCs and unveil that leukemic fusion genes require PcG proteins exerting an effect in concert to establish LSC-specific transcriptional profiles, which confer full leukemogenic activity on LSCs.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: M
authors.initials: M
authors.lastname: Takeuchi
authors.forename: M
authors.initials: M
authors.lastname: Negishi
authors.forename: H
authors.initials: H
authors.lastname: Oguro
authors.forename: H
authors.initials: H
authors.lastname: Ichikawa
authors.forename: A
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D007938:Leukemia / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000473:pathology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D009687:Nuclear Proteins / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics
chemical_list: C489421:Bmi1 protein, mouse; C474558:MLL-AF9 fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; C114093:TBX15 protein, mouse; D051788:Myeloid-Lymphoid Leukemia Protein; D063150:Polycomb Repressive Complex 1