Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF‐04449913 (PF‐913) is a selective, small‐molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof‐of‐concept and mechanism of action of PF‐913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF‐913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34⁺ cells than CD34⁻ cells. In vitro treatment with PF‐913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF‐913 attenuated the leukemia‐initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF‐913 modulated self‐renewal signatures and cell cycle progression. Furthermore, PF‐913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS‐5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia‐initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.

Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML). However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy. Gene set enrichment analysis (GSEA) revealed that PF-913 treatment affected the self-renewal signature and cell-cycle regulation associated with LSC-like properties. We then focused on the expression of a pluripotency factor, NANOG, because previous reports showed that a downstream effector in the Hh pathway, GLI, directly binds to the NANOG promoter and that the GLI-NANOG axis promotes stemness and growth in several cancers. In this study, we found that a change in NANOG transcripts was closely associated with GLI-target genes and NANOG transcripts can be a responsive biomarker during PF-913 therapy. Additionally, the treatment of AML with PF-913 holds promise, possibly through inducing quiescent leukemia stem cells toward cell cycling.

Rhabdomyolysis is characterized by a marked elevation of the creatine kinase (CK) levels and myoglobinuria, thus leading to renal dysfunction. Various viruses or bacteria can be etiologic agents, but mycosis has only rarely been reported to be a cause of rhabdomyolysis. In this report, we describe an adolescent male with acute myeloid leukemia who underwent allogeneic bone marrow transplantation and thereafter developed rhabdomyolysis and Candida parapsilosis fungemia almost at the same time. Following treatment for C. parapsilosis, the transaminase and CK levels both satisfactorily decreased. This case illustrates that C. parapsilosis infection may be a causative agent of rhabdomyolysis in immunocompromised patients.

Wnt signaling plays an important role in hematopoietic stem cell self-renewal and proliferation. Recent studies have revealed that the strength of the Wnt signaling pathway regulates normal hematop...