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Animal Models

Differential requirements for c-Myc in chronic hematopoietic hyperplasia and acute hematopoietic malignancies in Pten-null mice

Leukemia volume 25, pages 1857–1868 (2011)Cite this article

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Abstract

Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten (phosphatase and tensin homolog, deleted on chromosome ten)-knockout mice (Pten−/−). The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs that developed in Pten−/− mice, which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of phosphoinositide 3-kinase/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. However, owing to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte- to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies.

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Acknowledgements

We appreciate Dr Ignacio Moreno de Alborán of the Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Universidad Autónoma de Madrid, Madrid, Spain for his kindness in providing the Mycfx mouse line. We appreciate Dr Tak W Mak of the Campbell Family Institute for Breast Cancer Research, University of Toronto, Toronto, Canada, for his kindness in providing the Ptenfx mouse line. We appreciate the excellent animal care services provided by the staff of the Department of Comparative Medicine of Loyola University Medical Center. This work was supported by the NIH-R01 5R01HL95896-2, the NSFC Project 81071774, the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, the grant from Science and Technology Commission of Shanghai Municipality (10540503400), Shanghai Normal University Leading Disciplines Project (DZL808) and the Shanghai Leading Academic Discipline Project (S30406), as well as by a grant from the Jimmy Burns Foundation. The authors have no conflicting financial interests.

Author Contributions

JZ, YX, YG and ZZ performed most of the research and analyzed the data. SZ and WW performed some of the research. PB analyzed the data and wrote the paper. JZ designed the research, analyzed the data and wrote the paper.

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Authors and Affiliations

  1. Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China

    J Zhang & Z Zhang

  2. Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA

    J Zhang, Y Xiao, Y Guo, P Breslin, S Zhang, W Wei, Z Zhang & J Zhang

  3. Pathology Department, Loyola University Medical Center, Maywood, IL, USA

    J Zhang

  4. Department of Respiratory and Molecular Biology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China

    Y Guo

  5. Department of Biology, Loyola University Chicago, IL, Chicago, USA

    P Breslin

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Zhang, J., Xiao, Y., Guo, Y. et al. Differential requirements for c-Myc in chronic hematopoietic hyperplasia and acute hematopoietic malignancies in Pten-null mice. Leukemia 25, 1857–1868 (2011). https://doi.org/10.1038/leu.2011.220

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