c-Myb and its target Bmi1 are required for p190BCR ABL leukemogenesis in mouse and human cells

• Published in: Leukemia Vol. 26; no. 4; pp. 644 - 653
• Main Authors: Waldron, T, De Dominici, M, Soliera, A R, Audia, A, Iacobucci, I, Lonetti, A, Martinelli, G, Zhang, Y, Martinez, R, Hyslop, T, Bender, T P, Calabretta, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2012; Nature Publishing Group
• Subjects: Acute lymphoblastic leukemia; Alleles; Animal models; Animals; Biological and medical sciences; c-Myb protein; Cancer; Cancer cells; Cancer Research; Care and treatment; Cell Proliferation; Cell Transformation, Neoplastic - pathology; Colonies; Critical Care Medicine; Diagnosis; Ectopic expression; Fusion Proteins, bcr-abl - physiology; Gene expression; Gene targeting; Genes; Genetic aspects; Hematologic and hematopoietic diseases; Hematology; Hematopoiesis; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, B-Cell - etiology; Leukemia, B-Cell - pathology; Leukemogenesis; Lymphatic leukemia; Lymphocytes B; Lymphocytes T; Medical prognosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 7 - physiology; Myeloid leukemia; Nuclear Proteins - physiology; Oncology; original-article; Polycomb Repressive Complex 1; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-myb - physiology; Repressor Proteins - physiology; Stem cells; Transcription; Transcription factors; Transgenic mice; United States; Canada; United States > US; Montreal Quebec Canada; oncogene; transcription factor; stem cells; Human; Targeting; Hematology; Stem cell; Rodentia; Carcinogenesis; Signal transduction; Vertebrata; Mammalia; Mouse; BMI1 gene; Animal; C-Onc gene; Leukemogenesis; Transcription factor; Onc gene; Protooncogene
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.264

Expression of c-Myb is required for normal hematopoiesis and for proliferation of myeloid leukemia blasts and a subset of T-cell leukemia, but its role in B-cell leukemogenesis is unknown. We tested the role of c-Myb in p190 BCR/ABL -dependent B-cell leukemia in mice transplanted with p190 BCR/ABL -transduced marrow cells with a c-Myb allele (Myb f/d ) and in double transgenic p190 BCR/ABL /Myb w/d mice. In both models, loss of a c-Myb allele caused a less aggressive B-cell leukemia. In p190 BCR/ABL -expressing human B-cell leukemia lines, knockdown of c-Myb expression suppressed proliferation and colony formation. Compared with c-Myb w/f cells, expression of Bmi1, a regulator of stem cell proliferation and maintenance, was decreased in pre-B cells from Myb w/d p190 BCR/ABL transgenic mice. Ectopic expression of a mutant c-Myb or Bmi1 enhanced the proliferation and colony formation of Myb w/d p190 BCR/ABL B-cells; by contrast, Bmi1 downregulation inhibited colony formation of p190 BCR/ABL -expressing murine B cells and human B-cell leukemia lines. Moreover, c-Myb interacted with a segment of the human Bmi1 promoter and enhanced its activity. In blasts from 19 Ph 1 adult acute lymphoblastic leukemia patients, levels of c-Myb and Bmi1 showed a positive correlation. Together, these findings support the existence of a c-Myb–Bmi1 transcription-regulatory pathway required for p190 BCR/ABL leukemogenesis.