International Journal of Molecular Sciences Review The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities Samantha Bruno 1 , Manuela Mancini 2, Sara De Santis 1, Cecilia Monaldi 1, Michele Cavo 1,2 and Simona Soverini 1,* 1 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
[email protected] (S.B.);
[email protected] (S.D.S.);
[email protected] (C.M.);
[email protected] (M.C.) 2 Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy;
[email protected] * Correspondence:
[email protected] Abstract: Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and α metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1 and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the Citation: Bruno, S.; Mancini, M.; hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also De Santis, S.; Monaldi, C.; Cavo, M.; highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to Soverini, S.