Hedgehog and PI3K/Akt/mTOR Signaling Pathways Involvement in Leukemic Malignancies: Crosstalk and Role in Cell Death

The Hedgehog (Hh) and PI3K/Akt/mTOR signaling pathways play a pivotal role in driving the initiation and progression of various cancers, including hematologic malignancies such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). These pathways are often dysregulated in leukemia cells, leading to increased cell growth, survival, and drug resistance while also impairing mechanisms of cell death. In leukemia, the Hh pathway can be abnormally activated by genetic mutations. Additionally, the PI3K/Akt/mTOR pathway is frequently overactive due to genetic changes. A key aspect of these pathways is their interaction: activation of the PI3K/Akt pathway can trigger a non-canonical activation of the Hh pathway, which further promotes leukemia cell growth and survival. Targeted inhibitors of these pathways, such as Gli inhibitors and PI3K/mTOR inhibitors, have shown promise in preclinical and clinical studies.