Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41419472.
- Also identified by DOI 10.1038/s41467-025-67611-w and PMC identifier 12830621.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
To address the cellular origin of ecotropic virus integration site 1 (EVI1)-expressing aggressive KMT2A-rearranged acute myeloid leukaemia (AML) we integrate an Evi1-GFP reporter allele in the inducible iKMT2A-MLLT3 mouse model. We observe that a single injection of thrombopoietin (TPO) selectively increases the number of cycling Evi1<sup>+</sup> haematopoietic stem cells (HSC) and accelerates AML initiation. Comparison of mouse Evi1<sup>+</sup> KMT2-MLLT3<sup>+</sup> AML originating from TPO-stimulated HSC with human EVI1<sup>+</sup>AML reveals higher expression of HSC genes including IL12Rβ2 and INPP4B linked to poor disease outcome of patients of four large AML cohorts. Knockdown experiments show exclusive MECOM-dependency of human EVI1<sup>high</sup> KMT2A-rearranged OCI-AML4 cells while reduction of IL12Rβ2 also impairs clonogenic growth of EVI1<sup>low</sup> MOLM-13, THP-1 or HL-60 AML cells. Collectively, we show that exogenous factors like TPO can increase the susceptibility for iKMT2A-MLLT3-driven HSC-originating Evi1<sup>+</sup> AML expressing stem cell genes linked to transformation maintenance of cell lines, and poor disease outcome of patients.
Medical subject headings
- MDS1 and EVI1 Complex Locus Protein
- Leukemia, Myeloid, Acute
- Thrombopoietin
- Histone-Lysine N-Methyltransferase
- Myeloid-Lymphoid Leukemia Protein