BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells.
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.
Rizo
Aleksandra
A
Department of Hematology, University Medical Center Groningen, Groningen, The Netherland.
Horton
Sarah J
SJ
Olthof
Sandra
S
Dontje
Bert
B
Ausema
Albertina
A
van Os
Ronald
R
van den Boom
Vincent
V
Vellenga
Edo
E
de Haan
Gerald
G
Schuringa
Jan Jacob
JJ
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
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