Figure 2: UPR Signaling in Leukemia Initiation, Progression and Therapy Response.

Leukemic and pre-leukemic cells are exposed to harsh environmental conditions (hypoxia, ROS) that increase protein misfolding and trigger ER stress. Genetic alterations commonly observed in leukemia, such as BCR-ABL, PML-RARα or MYC mutations as well as other oncogenic signaling events, such as increased c-Jun levels, contribute to elevated UPR signaling in leukemias. UPR components can also be upregulated, putatively independent of ER stress in leukemia, e.g. by hypomethylation of UPR genes. All these events (red arrows) culminate to promote UPR signaling and leukemia cells are often characterized by high basal UPR signaling to increases the capacity of cells to cope with stress and restore ER homeostasis. The adaptive signaling events orchestrated by the UPR promotes leukemogenesis and progression by altering diverse cellular processes, from affecting cellular differentiation, as occurs in AML, to increased cell survival and therapy resistance in multiple disease types.

Exemplary alternate routes to maintain ER homeostasis are displayed (green arrows), where RUNX1 mutations decrease ribosome biogenesis, resulting in reduced ER protein load, thereby increasing the capacity of the ER to cope with stressful insults, which also endows RUNX1-mutated cells with increased survival and therapy resistance. Targeting the UPR thus could prevent leukemia progression and overcome resistance to standard therapeutic regimens.