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Acute Leukemias

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

Leukemia volume 26, pages 644–653 (2012)Cite this article

Abstract

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 p190BCR/ABL-dependent B-cell leukemia in mice transplanted with p190BCR/ABL-transduced marrow cells with a c-Myb allele (Mybf/d) and in double transgenic p190BCR/ABL/Mybw/d mice. In both models, loss of a c-Myb allele caused a less aggressive B-cell leukemia. In p190BCR/ABL-expressing human B-cell leukemia lines, knockdown of c-Myb expression suppressed proliferation and colony formation. Compared with c-Mybw/f cells, expression of Bmi1, a regulator of stem cell proliferation and maintenance, was decreased in pre-B cells from Mybw/d p190BCR/ABL transgenic mice. Ectopic expression of a mutant c-Myb or Bmi1 enhanced the proliferation and colony formation of Mybw/d p190BCR/ABL B-cells; by contrast, Bmi1 downregulation inhibited colony formation of p190BCR/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 Ph1 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 p190BCR/ABL leukemogenesis.

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Acknowledgements

We thank Dr Dimri (Department of Cancer Biology, Evanston Northwestern Healthcare Research Institute, Evanston, IL, USA) for the Bmi1-Luc plasmid and Dr Sankar Addya (Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA) for analysis of microarray data. This work was supported by National Cancer Institute Grants CA95111 and P0178890 (BC); and European LeukemiaNet, AIRC, AIL and Fondazione Del Monte di Bologna e Ravenna (GM and II); and NIAID Grant AI059294 (TPB).ARS was supported by a fellowship of the American-Italian Cancer Foundation (AICF) and is currently supported by a fellowship from Associazione Italiana Ricerca sul Cancro (AIRC). TW was supported by a National Institutes of Health pre-doctoral fellowship (T32-CA09683-14).

Author contributions

T Waldron performed most experiments and wrote the first draft of the manuscript. M De Dominici performed the experiments with human ALL lines. AR Soliera performed the luciferase and ChIP assays on the Bmi-1 promoter. I Iacobucci, A Leonetti and G Martinelli performed the real-time PCR studies on the ALL samples. Y Zhang and R Martinez performed microarray hybridization analyses. T Hyslop performed statistical analyses. TP Bender provided Mybf/d mice and help for the immunophenotype analyses. B Calabretta designed the experiments and wrote the manuscript.

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Authors and Affiliations

  1. Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    T Waldron, M De Dominici, A R Soliera, A Audia & B Calabretta

  2. Department of Hematology/Oncology, University of Bologna, Bologna, Italy

    I Iacobucci, A Lonetti & G Martinelli

  3. Department of Biological Technologies, Wyeth Research, Cambridge, MA, USA

    Y Zhang & R Martinez

  4. Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA, USA

    T Hyslop

  5. Department of Microbiology, University of Virginia Health System, Charlottesville, VA, USA

    T P Bender

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Correspondence to B Calabretta.

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This work is dedicated to the memory of Dr Alan M Gewirtz.

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Waldron, T., De Dominici, M., Soliera, A. et al. c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells. Leukemia 26, 644–653 (2012). https://doi.org/10.1038/leu.2011.264

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