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Chronic Myeloproliferative Neoplasias

BCR–ABL promotes neutrophil differentiation in the chronic phase of chronic myeloid leukemia by downregulating c-Jun expression

Leukemia volume 23, pages 1622–1627 (2009)Cite this article

Abstract

The mechanism that is responsible for mature neutrophil overproduction in the chronic phase (CP) of chronic myeloid leukemia (CML), a neoplastic disease of hematopoietic stem cells carrying a constitutively active tyrosine kinase BCR–ABL, remains obscure. In this study, microarray analysis revealed that c-Jun, a monopoiesis-promoting transcription factor, was downregulated in CML neutrophils. BCR–ABL directly inhibited c-Jun expression, as c-Jun downregulation in primary CML neutrophils and in the CML blast cell lines, KCL22 and K562, was reversed by the tyrosine kinase inhibitor imatinib. We established a myeloid differentiation model in KCL22 cells using zinc-inducible CCAAT/enhancer-binding protein (C/EBP)α (KCL22/α). Myeloid differentiation was observed in C/EBP-induced KCL22/α cells. Imatinib-induced c-Jun upregulation promoted the monocytic differentiation of KCL22/α cells. c-Jun knockdown in KCL22/α cells by a short interfering RNA redirected their differentiation from the monocytic to the neutrophilic lineage, even after imatinib treatment. A blockade of PI3K-Akt signaling with an Akt inhibitor upregulated c-Jun and induced the monocytic differentiation of KCL22, K562, and C/EBP-induced KCL22/α cells. Thus, BCR–ABL downregulates c-Jun expression by activating the PI3K-Akt pathway during CML-CP, thereby allowing C/EBPs to promote neutrophil differentiation.

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Acknowledgements

We thank Dr Hiroyuki Mano for the KCL22 cell line and Yukiharu Banba for cytospin imaging.

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan

    S Kobayashi, F Kimura, Y Osawa, A Kobayashi, K Sato & K Motoyoshi

  2. Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Suntogun, Shizuoka, Japan

    T Ikeda

  3. Division of Immunology, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-ku, Nagoya, Japan

    H Torikai

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  1. S Kobayashi
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Correspondence to K Motoyoshi.

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Supplementary information accompanies the paper on Leukemia website (http://www.nature.com/leu/)

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Kobayashi, S., Kimura, F., Ikeda, T. et al. BCR–ABL promotes neutrophil differentiation in the chronic phase of chronic myeloid leukemia by downregulating c-Jun expression. Leukemia 23, 1622–1627 (2009). https://doi.org/10.1038/leu.2009.74

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