Acute myeloid leukemia (AML) primarily affects older adults and is driven by hundreds of mutations that disrupt blood cell development. Its treatment remains challenging, as chemotherapy often fails to eradicate leukemic stem cells (LSCs), leading to relapse. In this thesis, we investigate potential markers on LSCs and mature leukemic cells to identify new therapeutic opportunities.
We reveal how AML cells remodel the bone marrow (BM) niche via IL1RAP, a surface receptor upregulated in AML. We demonstrate that IL1RAP drives the secretion of inflammatory cytokines that impair normal hematopoiesis while preserving leukemic cell proliferation. Blocking this pathway with Anakinra, an IL1 receptor antagonist, partially restores normal blood cell production.
We also investigate DNMT3A, a frequently mutated DNA methyltransferase in AML. While DNMT3A mutations often expand over time, we show that overexpression of DNMT3A triggers DNA damage, marked by the formation of γH2A.X foci. This highlights the importance of proper in vitro models to recapitulate in vivo phenomena.
Furthermore, we explore how Polycomb Group (PcG) proteins, specifically RING1B and PCGF1, regulate the DNA damage response (DDR). We show that RING1B and PCGF1 are recruited to DNA breaks, where they modulate chromatin structure and influence the recruitment of repair factors.
Finally, we investigate GPR114, a G-protein-coupled receptor, in endoplasmic reticulum (ER) calcium signaling. We reveal that GPR114 interacts with the Sigma-1 receptor, controlling calcium release from the ER. Cells with inhibited GPR114 exhibit defective unfolded protein responses and impaired survival.
Collectively, our findings shed light on critical mechanisms of leukemogenesis, offering new opportunities for targeted therapy.
