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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD34 / metabolism*
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Female
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Fetal Blood / cytology*
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism*
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Gene Expression
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Gene Expression Regulation, Leukemic
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / etiology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Mice, SCID
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Polycomb Repressive Complex 1
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Tumor Cells, Cultured
Substances
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Antigens, CD34
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BMI1 protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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Polycomb Repressive Complex 1
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Fusion Proteins, bcr-abl