Yukiko Osawa

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)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.

Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation.

Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation

Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis

Myelofibrosis (MF) may be caused by various pathogenic mechanisms such as elevation in circulating cytokine levels, cellular interactions and genetic mutations. However, the underlying mechanism of MF still remains unknown. Recent studies have revealed that fibrocytes, the spindle-shaped fibroblast-like hematopoietic cells, and the thrombopoietin (TPO)/myeloproliferative leukemia protein (MPL; TPO receptor) signaling pathway play a certain role in the development of MF. In the present study, we aimed to investigate the relationship between fibrocytes and MPL activation. We showed that TPO or a TPO receptor agonist directly induces fibrocyte differentiation using murine fibrocyte cell lines and a murine MF model. Conversely, elimination of macrophages expressing MPL by clodronate liposomes reversed the MF phenotype of the murine model, suggesting that fibrocyte differentiation induced by MPL activation contributes to the progression of MF. Furthermore, we revealed that SLAMF7high MPLhigh monocytes in human peripheral blood mononuclear cells were possible fibrocyte precursors and that these cells increased in number in MF patients not treated with ruxolitinib. Our findings confirmed a link between fibrocytes and the TPO/MPL signaling pathway, which could result in a greater understanding of the pathogenesis of MF and lead to the development of novel therapeutic interventions.