Proteomic characterization of measurable residual disease (MRD) in acute myeloid leukemia (AML)

• Applicant: Dr. Laura Schmalbrock
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528299520

Extensive sequencing studies revealed the genetic background of acute myeloid leukemia (AML) and improved our understanding of the biology of the disease. Despite recent advances in the treatment of AML the prognosis for most patients remains to be poor and most patients will eventually relapse. Residual AML cells that persist upon treatment, termed as measurable residual disease (MRD), are of acknowledged clinical importance for outcome and disease monitoring in AML. Molecular characteristics of persistent AML cells that give raise to relapse are however incompletely understood. Furthermore, the role of differentially expressed surface proteins for maintenance of cell persistence and interactions between leukemic cells and the bone marrow (BM) niche needs further investigation. While many studies explored alterations of the genome and transcriptome in drug resistance, less is known about the significance of aberrant proteomes and post-translational modifications (PTM) regulating disease persistence in AML. Supported by recent advances of mass spectrometry (MS) based approaches and improved analysis tools, the characterization of proteome alterations is of increasing interest for a comprehensive understanding of drug resistance and the discovery of potential new therapeutic targets in AML. In the proposed project, we aim to investigate disease persistence and MRD state using proteogenomics to enhance our understanding of mechanisms leading to drug resistance and disease recurrence in AML. Using ultra-sensitive MS and RNA sequencing, we will comprehensively characterize aberrant total and surface proteomes in AML MRD. Persistent cells will be assessed in patient-derived xenograft AML mouse models after treatment using chemical label tracing and analyzed with sensitive MS to define aberrant proteomes that might contribute to cell quiescence. In parallel, we will analyze BM samples of AML patients collected at diagnosis and during treatment with sensitive MS to explore differences between bulk leukemia and resistant AML cells. With this analysis, we aim to define molecular mechanisms controlling cell persistence in AML on a proteogenomic level. Since aberrantly expressed surface markers in persistent AML cells represent potential targets for MRD eradication, we further aim to investigate the impact of selected aberrantly expressed surface proteins for maintenance of cell quiescence. Using genetic modification of selected surface proteins, we will functionally assess the influence of surface protein expression for leukemia initiation and drug resistance. Focusing on surface markers associated with altered energy metabolism, we aim to define this potential vulnerability for therapeutic targeting of persistent cells. Overall, the aim of the proposal is to define aberrant (surface-) proteomes and PTMs in AML cell quiescence using proteogenomics for a better understanding of resistance mechanisms in AML and the discovery of new therapeutic approaches.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Alex Kentsis