Mediators of the Unfolded Protein Response defining therapeutic targets in acute myeloid leukemia (AML)

• Applicant: Privatdozentin Dr. Mirle Schemionek-Reinders, since 6/2016
• Subject Area: Hematology, Oncology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290250676

Acute myeloid leukemia (AML) is a clonal hematological malignancy that originates from a single transformed cell. The acquisition of critical genetic (translocations e.g. PML-RARalpha, AML1-ETO; FLT3 mutations) and epigenetic changes (e.g. DNTMs) causes disturbances in key growth-regulatory pathways. Our recently published studies identified the unfolded protein response (UPR), a cellular machinery for scavenging ER stress, to be critical for specific acute leukemias, initially focusing on acute lymphoblastic leukemia (ALL). Our published results showed an oncogene-specific function of UPR-pathways. Here, our novel preliminary findings expand our studies and unravel a similar vulnerability of AML cells towards pharmacological targeting of UPR-based therapy. Nevertheless the exact function of individual UPR pathways, namely IRE-1alpha / XBP1 and PERK are unclear. Therefore, we suggest in aim 1 to test the impact of the genetic loss of the UPR network on AML survival. We will mainly focus on the two predominant pathways Xbp1 and Perk and their important role within the leukemia stem cell hierarchy. In aim 2, we will then test how UPR pathways interact with other important survival pathways. We will test, how UPR genes crosstalk with hypoxia and stem cell-related pathways such as HIF members and beta-catenin / WNT. Taken together, these studies will allow us the question, how UPR pathways are targetable in therapeutically challenging AML populations and help to bridge new therapeutic interventions.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Behzad Kharabi Masouleh, until 5/2016