BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells

Aleksandra Rizo; Sarah J Horton; Sandra Olthof; Bert Dontje; Albertina Ausema; Ronald van Os; Vincent van den Boom; Edo Vellenga; Gerald de Haan; Jan Jacob Schuringa

doi:10.1182/blood-2010-02-270660

BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells

Blood. 2010 Nov 25;116(22):4621-30. doi: 10.1182/blood-2010-02-270660. Epub 2010 Aug 19.

Authors

Aleksandra Rizo¹, Sarah J Horton, Sandra Olthof, Bert Dontje, Albertina Ausema, Ronald van Os, Vincent van den Boom, Edo Vellenga, Gerald de Haan, Jan Jacob Schuringa

Affiliation

¹ Department of Hematology, University Medical Center Groningen, Groningen, The Netherland.

PMID: 20724541
DOI: 10.1182/blood-2010-02-270660

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

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD34 / metabolism*
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Female
Fetal Blood / cytology*
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism*
Gene Expression
Gene Expression Regulation, Leukemic
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / pathology
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / etiology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Mice
Mice, SCID
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Polycomb Repressive Complex 1
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Tumor Cells, Cultured

Substances

Antigens, CD34
BMI1 protein, human
Nuclear Proteins
Proto-Oncogene Proteins
Repressor Proteins
Polycomb Repressive Complex 1
Fusion Proteins, bcr-abl