Hedgehog Signaling in Myeloid Malignancies

SIMPLE SUMMARY: The Hedgehog signaling pathway is aberrantly activated in many myeloid malignancies, and pathway inhibition is clinically beneficial in specific patients with acute myeloid leukemia. However, even with the approval of these agents, the role of Hedgehog signaling in other myeloid disorders is less clear. In this review, we summarize the laboratory studies that have examined Hedgehog signaling in normal and malignant hematopoiesis as well as the clinical studies that have been carried out in several myeloid leukemias. Finally, we explore potential strategies to further expand the use of pathway inhibitors as therapies for these diseases. ABSTRACT: Myeloid malignancies arise from normal hematopoiesis and include several individual disorders with a wide range of clinical manifestations, treatment options, and clinical outcomes. The Hedgehog (HH) signaling pathway is aberrantly activated in many of these diseases, and glasdegib, a Smoothened (SMO) antagonist and HH pathway inhibitor, has recently been approved for the treatment of acute myeloid leukemia (AML). The efficacy of SMO inhibitors in AML suggests that they may be broadly active, but clinical studies in other myeloid malignancies have been largely inconclusive. We will discuss the biological role of the HH pathway in normal hematopoiesis and myeloid malignancies and review clinical studies targeting HH signaling in these diseases. In addition, we will examine SMO-independent pathway activation and highlight potential strategies that may expand the clinical utility of HH pathway antagonists.