Understanding the Hedgehog Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Necessary Step toward a Cure

Abstract

A better understanding of how signaling pathways govern cell fate is fundamental to advances in cancer development and treatment. The initialization of different tumors and their maintenance are caused by the deregulation of different signaling pathways and cancer stem cell maintenance. Quiescent stem cells are resistant to conventional chemotherapeutic treatments and, consequently, are responsible for disease relapse. In this review we focus on the conserved Hedgehog (Hh) signaling pathway which is involved in regulating the cell cycle of hematopoietic and leukemic stem cells. Thus, we examine the role of the Hh signaling pathway in normal and leukemic stem cells and dissect its role in acute myeloid leukemia. We explain not only the connection between illness and the signaling pathway but also evaluate innovative therapeutic approaches that could affect the outcome of patients with acute myeloid leukemia. We found that many aspects of the Hedgehog signaling pathway remain unknown. The role of Hh has only been proven in embryo and hematopoietic stem cell development. Further research is needed to elucidate the role of GLI transcription factors for therapeutic targeting. Glasdegib, an SMO inhibitor, has shown clinical activity in acute myeloid leukemia; however, its mechanism of action is not clear.

Macrophages and cancer stem cells: a malevolent alliance

“…Glasdegib, an inhibitor of Hedgehog, has been approved by FDA and showed clinical activity in acute myeloid leukemia (Lainez-Gonzalez et al 2021 ).…”

Can the New and Old Drugs Exert an Immunomodulatory Effect in Acute Myeloid Leukemia?

“…The Hedgehog (HH) family of intercellular signaling proteins is of crucial importance in embryonic development, tissue polarity control and stem cell maintenance [101]. Aberrations of the HH pathway are involved in tumorigenesis [33].…”

Profile of Glasdegib for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML): Evidence to Date

“…The majority of these roles appear to be epigenetically silenced in most human tissues after early development; roles in adults include extrathymic T cell development and pro-survival signaling in germinal center B cells, however the existence of an active role in adult hematopoiesis is unclear. [15][16][17] The human Hh signaling cascade, illustrated in Figure 1, begins with three ligands: Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH). These ligands bind to the transmembrane protein Patched (PTCH), releasing its inhibition of the 7-transmembrane G-like protein-couples receptor SMO.…”