Pathomechanisms inducing aberrant self-renewal and chemoresistance in GPR56high DNMT3A, NPM1, and FLT3-ITD triple mutated acute myeloid leukemia.

• Applicant: Dr. Caroline Pabst
• Subject Area: Hematology, Oncology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 327094337

Acute myeloid leukemia (AML) frequently presents without cytogenetic alterations (cytogenetically normal (CN)-AML). In this genetic subgroup knowledge about molecular genetic aberrations has become crucial for our understanding of the underlying pathomechanisms and for risk stratification to guide therapy decisions. DNMT3A, NPM1, and FLT3 belong to the most frequently mutated genes in CN-AML, but little is known about the co-occurrence of all three mutations (hereafter called triple AML DNMT3A/NPM1/FLT3-ITD). We found that triple AML is characterized by very high leukemia stem cell frequencies, short survival, and a unique GPR56highCD34low immunophenotype. Based on the literature and our findings we hypothesize that triple AML represents a distinct subgroup of CN-AML, in which these three mutations synergize to induce self-renewal and chemoresistance pathways. We propose to elucidate these pathomechanisms in three steps. First, we will analyze and model the transcriptomic signature induced by these three mutations in primary patient samples, inducible triple knock-in mouse models, and in genetically engineered human CD34+ cells. Using functional in vitro and in vivo assays we will determine which of the genes specifically upregulated in triple AML confer self-renewal and chemoresistance. Finally, we aim to use these novel findings to develop therapeutic approaches to specifically target leukemia stem cells in triple mutated AML. Taken together, this project aims to identify and characterize key regulators of self-renewal and chemoresistance in triple mutated AML DNMT3A/NPM1/FLT3-ITD.

• DFG Programme: Research Grants