Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome

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⁺ haematopoietic stem cells (HSC) and accelerates AML initiation. Comparison of mouse Evi1⁺ KMT2-MLLT3⁺ AML originating from TPO-stimulated HSC with human EVI1⁺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^high KMT2A-rearranged OCI-AML4 cells while reduction of IL12Rβ2 also impairs clonogenic growth of EVI1^low 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⁺ AML expressing stem cell genes linked to transformation maintenance of cell lines, and poor disease outcome of patients.