Amélie De Maesschalck

AML is a heterogeneous hematologic malignancy characterized by uncontrolled proliferation and halted differentiation of myeloid progenitor cells. Among its various subtypes, AML with KMT2A rearrangements (KMT2A-r) is an aggressive, prognostically unfavorable subtype. KMT2A-r AML is defined by abnormal epigenetic regulation due to formation of chimeric proteins activating oncogenic pathways like HOXA and MEIS1. These fusion proteins recruit cofactors like Menin and DOT1L, driving leukemogenesis through aberrant histone methylation.
Advances in differentiation therapy targeting these epigenetic dependencies have led to clinical success, including FDA approval of the Menin inhibitor Revumenib. This drug triggers a heavy differentiation event in AML cells, causing a brief spike in cell counts before the leukemic cells die and remission occurs. Mechanistically, it breaks the interaction of MEN1 with methyltransferase-2A (KMT2A), which methylates lysine 4 of histone H3. This interaction is essential in leukemias driven by KMT2A-r or nucleophosmin 1 mutation (NPM1m). Therefore, Revumenib is only approved for these AML subtypes.
Non-terminally differentiated myeloid cells, mostly cells with a higher stemness, are the main drivers of this differentiation problem in AML and the proteins, histone posttranslational modifications (hPTMs) and metabolites work coordinately to define this molecular phenotype. ProGenTomics developed a multi-omics mass spectrometry (MS)-based approach that integrates these molecular fractions, extracted from one single cell pellet: the histone epigenome, metabolome and proteome. This approach was applied to a cohort of 18 AML cell lines in collaboration with Prof. Tim Lammens, yielding a coherent dataset that enables the identification of key molecular drivers of AML.
The aim of my PhD project is to apply our newly established multi-omics workflow to a timelapse experimental design to study causation during differentiation in six AML cell lines. These six AML cell lines - 2 KMT2A-r, 1 NPM1-mutant and 3 non-KMT2A-r cell lines - are treated with Revumenib. By combining these three molecular layers across various timepoints, this comprehensive dataset enables characterization of dynamic relationships underlying differentiation. Ongoing analyses aim to identify coordinated molecular programs and regulatory interactions that drive AML cell state transitions, providing a framework for the discovery of new differentiation-based therapeutic strategies.
 

• Master of Science in drug development
   

• Lab address: Ottergemsesteenweg 460, Building A, B-9000 Gent
• ProGenTomics
• Amélie De Maesschalck is interested to receive invitations for presentations or talks