Abstract
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.
Highlights
The Hedgehog (Hh) signaling pathway is linked to tumorigenesis and is aberrantly activated in a variety of cancers [1,2]
Our research implies that Hedgehog inhibitor PF-913 treatment can modulate self-renewal and cell-cycling status during treatment with acute myeloid leukemia (AML)
We investigated the effects of Hedgehog signaling inhibitors on signatures in primary AML cells using PF-913 monotherapy patients’ bone marrow samples
Summary
The Hedgehog (Hh) signaling pathway is linked to tumorigenesis and is aberrantly activated in a variety of cancers [1,2]. Hh signaling components are reported to be expressed in acute myeloid leukemia (AML) cells [4,5]. The activity of the Hh signaling pathway is thought to be required for the maintenance of a leukemia stem cell (LSC) population at least in some experimental systems [5,6,7]. The eradication of these cells may be essential for reducing the recurrence of disease, implying that targeting the Hh signaling pathway may be the. 22..11..GGeenneeEExxpprreessssiioonnPPrrooffiilliinngg ffrroomm AAMMLL PPaattiieennttss dduurriinngg TTrreeaattmmeenntt wwiitthh PPFF--991133 MMoonnootthheerraappyy. UUssiningg bboonnee mmaarrrrooww lleeuukkeemmiiaa cceellllss ddeerriivveedd ffrroomm tthhrreeee AAMMLL//MMRRCC ppaattiieennttss uunnddeerr PPFF--991133 mmoonnootthheerraappyy,,wweeccoonndduucctteeddGGSSEEAA.
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