Drugging the unfolded protein response in acute leukemias

Abstract

The unfolded protein response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, is mediated by three major stress sensors IRE-1α, PERK, and ATF6α. Studies described the UPR as a critical network in selection, adaptation, and survival of cancer cells. While previous reviews focused mainly on solid cancer cells, in this review, we summarize the recent findings focusing on acute leukemias. We take into account the impact of the underlying genetic alterations of acute leukemia cells, the leukemia stem cell pool, and provide an outline on the current genetic, clinical, and therapeutic findings. Furthermore, we shed light on the important oncogene-specific regulation of individual UPR signaling branches and the therapeutic relevance of this information to answer the question if the UPR could be an attractive novel target in acute leukemias.

Fig. 1

A schematic overview on how PML-RARα causes ER stress in AML is provided. Here, under physiological conditions, RARα can dissociate from coreceptors such as N-CoR. In PML-RARα⁺ AML, the binding is significantly increased. This leads to a conformational change of the N-CoR protein. The misfolded N-CoR protein is degraded by ERAD through activation of ATF6α. Through the lack of soluble and functional N-CoR, protein myeloid differentiation is prevented and activity of the tumor suppressor MAD is reduced

Fig. 2

The expression profile of different UPR genes is shown by microarray analysis in HSC and different progenitor populations (multipotent progenitors (MPP), common myeloid progenitors (CMP), multipotent lymphoid progenitors (MLP), megakaryocytic-erythroid progenitors (MEP) and granulocyte-monocyte progenitors (GMP). The hierarchical tree is based on van Galen et al.

Fig. 3

A schematic overview of the UPR network and the currently available inhibitors targeting the individual signaling molecules and subsequent pathways