The hedgehog pathway in hematopoiesis and hematological malignancy

Abstract

The Hedgehog (HH) pathway is a promising therapeutic target in hematological malignancies. Activation of the pathway has been tied to greater chances of relapse and poorer outcomes in several hematological malignancies and inhibiting the pathway has improved outcomes in several clinical trials. One inhibitor targeting the pathway via the protein Smoothened (SMO), glasdegib, has been approved by the FDA for use with a low dose cytarabine regiment in some high-risk acute myeloid leukemia patients (AML). If further clinical trials in glasdegib produce positive results, there may soon be more general use of HH inhibitors in the treatment of hematological malignancies.While there is clinical evidence that HH inhibitors may improve outcomes and help prevent relapse, a full understanding of any mechanism of action remains elusive. The bulk of AML cells exhibit primary resistance to SMO inhibition (SMOi), leading some to hypothesize that that clinical activity of SMOi is mediated through modulation of self-renewal and chemoresistance in rare cancer stem cells (CSC). Direct evidence that CSC are being targeted in patients by SMOi has proven difficult to produce, and here we present data to support the alternative hypothesis that suggests the clinical benefit observed with SMOi is being mediated through stromal cells in the tumor microenvironment.This paper's aims are to review the history of the HH pathway in hematopoiesis and hematological malignancy, to highlight the pre-clinical and clinical evidence for its use a therapeutic target, and to explore the evidence for stromal activation of the pathway acting to protect CSCs and enable self-renewal of AML and other diseases. Finally, we highlight gaps in the current data and present hypotheses for new research directions.

Keywords: GLI1; Gli3; acute myeloid leukemia; glasdegib; hedgehog (Hh); hematological malignancy; hematopoiesis; smoothened inhibition.

Figure 1

A representation of the canonical HH signaling in the presence and absence of a HH ligand. (A) With the ligands absent, PTCH prevents SMO from translocating to the primary cilium. In the absence of SMO, the full-length forms of GLI2 and GLI3 are phosphorylated by PKA, and then processed into their repressor forms, which inhibit downstream transcription. (B) When ligands are present, they are bound by PTCH and both are internalized and degraded. This allows the translocation of SMO to the tip of the primary cilium, where it processes the full-length forms of the GLI proteins into their activator forms, which then promote transcription of downstream targets in the nucleus. Created in BioRender.

Figure 2

An illustration of the types of aberrant HH signaling. (A) In type I signaling, the Hh pathway is active despite the absence of the Hh ligand. (B) In type II or autocrine signaling tumor cells both produce and bind the ligands. (C) In type IIIa or paracrine signaling tumor cells produce ligands that activate HH signaling in the stroma, which in turn produces a more favorable niche for the tumor cells or cancer stem cells. (D) In type IIIb or reverse paracrine signaling the stroma produce ligands to activate HH signaling in the tumor cells. Created in BioRender.