A stem cell differentiation model reveals two alternative fates in CBFA2T3::GLIS2-driven acute megakaryoblastic leukemia initiation
Summary
The CBFA2T3::GLIS2 (CG) fusion protein causes aggressive pediatric acute megakaryoblastic leukemia (AMKL). Although dysregulated molecular pathways in AMKL have been identified, their role in early pre-leukemic transformation remains poorly understood. We developed a disease model utilizing genetically modified human induced pluripotent stem cells (hiPSC) physiologically and conditionally expressing CG. Using in vitro differentiation and single-cell multi-omics, we captured the impact of oncogene activity on gene-regulatory networks during hematopoiesis. We discovered that CG interferes with myelopoiesis through two alternative routes: by locking aberrant megakaryocyte progenitors (aMKP) in a proliferative state, or by impeding differentiation of aberrant megakaryocytes (aMK). Transcriptionally and functionally, aMKPs mimic CG-AMKL cells and establish a self-renewal network with co-factors GATA2, ERG, and DLX3. In contrast, aMKs partially sustain regulators of MK maturation but fail to complete differentiation due to repression of factors like NFE2, SPI1, GATA1 and LYL1. These insights may inform new strategies for targeting AMKL cell states. © 2025. The Author(s).
| Authors | Shoeb MR, Schinnerl D, Shaw LE, Farlik M, Strehl S, Halbritter F, Fortschegger K |
|---|---|
| Journal | Communications biology |
| Publication Date | 2025 Aug 27;8(1):1289 |
| PubMed | 40866546 |
| PubMed Central | PMC12391542 |
| DOI | 10.1038/s42003-025-08730-4 |