Crosstalk Between the PI3K/AKT/mTOR Signaling Pathway And The HIF-1α/CA9 Axis and its Significance in Leukemogenesis of Acute Myeloid Leukemia

Review article

Abstract

Acute myeloid leukemia (AML) is a refractory heterogeneous hematological disease. Leukemic stem cells (LSCs) in the CD34+CD38- AML cells are causes of therapy resistance and relapse. Progression of LSCs to overt AML is primarily dependent on cell-intrinsic oncogenic alterations. However, bone marrow microenvironment (BMM) also affects leukemogenesis of AML. In fact, activated expression of hypoxia-inducible factor 1α (HIF-1α) and carbonic anhydrase IX (CA9) is observed in AML. In addition, constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling pathway in AML is also detected. This review article aims to summarize the crosstalk between aberrantly activated PI3K/AKT/mTOR signaling and the HIF-1α /CA9 axis in AML for clarification of AML leukemogenesis. Aberrant activation of PI3K/AKT/mTORC1 signaling that is induced by suppression of phosphatase and tensin homolog (PTEN), activating mutation of FLT3, autocrine/paracrine activation of VEGF/VEGFR-2 signaling and autocrine activation of IGF-1/IGF-1R signaling activates translation of HIF-1α mRNA via activation of 4E-BPs and S6Ks, and transcription of HIF-1α mRNA via activation of nuclear factor kappa B (NF-κB). These mechanisms of the crosstalk between the PI3K/AKT/mTORC1 signaling and the HIF-1α/CA9 axis finally activate CA9. Further research on this crosstalk is required for development of novel therapies against AML LSCs.