1. ¹Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
2. ²Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Suntogun, Shizuoka, Japan
3. ³Division of Immunology, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-ku, Nagoya, Japan

Correspondence: Professor K Motoyoshi, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail: motoyosi@ndmc.ac.jp

Received 12 August 2008; Revised 18 February 2009; Accepted 3 March 2009; Published online 9 April 2009.

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) (KCL22/). Myeloid differentiation was observed in C/EBP-induced KCL22/ cells. Imatinib-induced c-Jun upregulation promoted the monocytic differentiation of KCL22/ cells. c-Jun knockdown in KCL22/ 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/ 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.