title: Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells.
abstract: The characterization and targeting of Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL)-initiating cells remains unresolved. Expression of the polycomb protein Bmi1 is up-regulated in patients with advanced stages of chronic myelogenous leukemia (CML). We report that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter-driven, self-renewing, leukemia-initiating cells to result in B-lymphoid leukemia (B-ALL) in vivo. In vitro, highly proliferating and serially replatable myeloid and lymphoid colony-forming cultures could be established from BCR-ABL and Bmi1 coexpressing progenitors. However, unlike in vivo expanded CML B-lymphoid progenitors, hematopoietic stem cells, or multipotent progenitors, coexpressing BCR-ABL and Bmi1 did not initiate or propagate leukemia in a limiting dilution assay. Inducible genetic attenuation of BCR-ABL reversed Bmi1-driven B-ALL development, which was accompanied by induction of apoptosis of leukemic B-lymphoid progenitors and by long-term animal survival, suggesting that BCR-ABL is required to maintain B-ALL and that BCR-ABL and Bmi1 cooperate toward blast transformation in vivo. Our data indicate that BCR-ABL targeting itself is required to eradicate Ph(+)/Bmi1(+) B-ALL-initiating cells and confirm their addiction to BCR-ABL signaling.
authors.affiliation: Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
authors.forename: Amitava
authors.initials: A
authors.lastname: Sengupta
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Ficker
authors.forename: Susan K
authors.initials: SK
authors.lastname: Dunn
authors.forename: Malav
authors.initials: M
authors.lastname: Madhu
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C489421:Bmi1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D016044:Fusion Proteins, bcr-abl
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