Figure 2: Role of hypoxia in leukemic stem cell maintenance. Under normoxia conditions, the alpha-subunit of hypoxia inducible factor (HIF-alpha) undergoes an oxygen-dependent hydroxylation by the enzyme prolyl hydroxylase (PHD). The hydroxylated form of HIF-alpha is recognized by the von Hippel–Lindau protein (pVHL); this interaction allows for ubiquitination and proteasomal degradation of HIF-alpha. Under hypoxic conditions, the hydroxylation and subsequent ubiquitination and degradation of HIF-alpha do not take place. Therefore, HIF-alpha is able to interact with the beta-subunit of hypoxia inducible factor (HIF-beta), forming a heterodimeric complex that can promote transcription of specific genes called hypoxia responsive elements (HREs). These genes encode for proteins with antiapoptotic (e.g., Bcl-2) and prosurvival (e.g., c-Kit and VEGF) functions. HREs also encode for CXCR4 and CXCL12, which play an important role in LSC homing and preservation. The ability of venetoclax, a potent Bcl-2 inhibitor, to induce LSC apoptosis is explained by the high level of Bcl-2 expression on LSCs.