title: BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells.
abstract: The major limitation for the development of curative cancer therapies has been an incomplete understanding of the molecular mechanisms driving cancer progression. Human models to study the development and progression of chronic myeloid leukemia (CML) have not been established. Here, we show that BMI1 collaborates with BCR-ABL in inducing a fatal leukemia in nonobese diabetic/severe combined immunodeficiency mice transplanted with transduced human CD34(+) cells within 4-5 months. The leukemias were transplantable into secondary recipients with a shortened latency of 8-12 weeks. Clonal analysis revealed that similar clones initiated leukemia in primary and secondary mice. In vivo, transformation was biased toward a lymphoid blast crisis, and in vitro, myeloid as well as lymphoid long-term, self-renewing cultures could be established. Retroviral introduction of BMI1 in primary chronic-phase CD34(+) cells from CML patients elevated their proliferative capacity and self-renewal properties. Thus, our data identify BMI1 as a potential therapeutic target in CML.
authors: Department of Hematology, University Medical Center Groningen, Groningen, The Netherland.
authors: Aleksandra
authors: A
authors: Rizo
authors: Sarah J
authors: SJ
authors: Horton
authors: Sandra
authors: S
authors: Olthof
authors: Bert
authors: B
authors: Dontje
authors: Albertina
authors: A
authors: Ausema
authors: Ronald
authors: R
authors: van Os
authors: Vincent
authors: V
authors: van den Boom
authors: Edo
authors: E
authors: Vellenga
authors: Gerald
authors: G
authors: de Haan
authors: Jan Jacob
authors: JJ
authors: Schuringa
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018952:Antigens, CD34; C069077:BMI1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D016044:Fusion Proteins, bcr-abl