BCR-ABL promotes neutrophil differentiation in the chronic phase of chronic myeloid leukemia by downregulating c-Jun expression.
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)alpha (KCL22/alpha). Myeloid differentiation was observed in C/EBP-induced KCL22/alpha cells. Imatinib-induced c-Jun upregulation promoted the monocytic differentiation of KCL22/alpha cells. c-Jun knockdown in KCL22/alpha 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/alpha 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.
Kobayashi
S
S
Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Kimura
F
F
Ikeda
T
T
Osawa
Y
Y
Torikai
H
H
Kobayashi
A
A
Sato
K
K
Motoyoshi
K
K
D001549:Benzamides; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000473:pathology*; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology
D001549:Benzamides; D022763:CCAAT-Enhancer-Binding Protein-alpha; D010879:Piperazines; D016755:Proto-Oncogene Proteins c-jun; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D051057:Proto-Oncogene Proteins c-akt