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.

症例は71歳女性. 全身倦怠感を主訴にX年5月に近医を受診, 腎機能障害を認め翌日に当科紹介受診となった. 受診時Cre 7.49mg/dL, M蛋白血症と胸腹部単純CT検査にて膀胱壁肥厚と両側水腎症を認めた. 両側水腎症に対して両側尿管カテーテルを挿入し, 右内頸静脈よりバスキュラーアクセスを留置して緊急血液透析を施行した. 骨髄検査の結果, 多発性骨髄腫と診断, 膀胱壁肥厚は粘膜下腫瘍であり生検により多発性骨髄腫の髄外病変と診断した. 多発性骨髄腫と診断後にBD (ボルテゾミブ＋デキサメタゾン) 療法を開始. 腎機能は緩徐に改善していき, 血液透析からは離脱し得た. 多発性骨髄腫に膀胱内髄外病変を合併することは非常に稀であり, 文献的考察も含めて報告する.

Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in maintenance of the leukemic stem cells (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO) regulating the Hh pathway. Treatment with PF-913 has shown promising results in the early phase study of acute myeloid leukemia (AML). However, the detailed mode of action and biomarkers remain to be elucidated.

Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in a variety of cancers, and required for maintenance of the leukemic stem cell (LSC) populations in several experimental systems. Cumulative evidence suggests that dormant self-renewing LSC contribute to acute myeloid leukemia (AML) propagation and relapse by evading conventional chemotherapies that target cycling cells. PF-913 is a novel oral small molecule inhibitor that selectively binds and targets Smoothened (SMO), a membrane protein regulating the Hh pathway. Treatment with PF-913 has shown promising results regarding safety, tolerability, and early signs of efficacy in AML patients. However, the detailed mechanisms and biomarkers remain to be elucidated in AML therapy. Results: In primary AML cells, the Hh signaling pathway was activated more in CD34⁺ cells than CD34⁻ cells. Ex vivo-treatment with PF-913 in AML cells induced minimal cell death as well as decrease of the quiescent cell population. In vivo-treatment with PF-913 attenuated leukemia-initiation potential in AML cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Also in the colony-assay system using primary AML cells, treatment with PF-913 reduced serially colony formation. Comprehensive Gene Set Enrichment Analysis (GSEA) revealed that PF-913 treatment modulated embryo stem (ES) cell-like signature in primary AML cells. Moreover, combined treatment with PF-913 abrogated resistance to Ara-C in AML cell lines co-cultured with HS-5 stromal cells and sensitized AML cells to Ara-C in the cutaneous tumor system. Conclusions: Our findings imply that PF-913 treatment can attenuate the leukemia-initiation potential in AML cells, and can also improve AML therapy through sensitizing dormant LSC to chemotherapy and overcoming the resistance in the bone marrow microenvironment.