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

## TL;DR

This study shows that thrombopoietin increases the risk of a specific type of aggressive leukemia by boosting stem cell activity and promoting cancer-linked genes.

## Contribution

The study identifies thrombopoietin as a factor that accelerates leukemia initiation from stem cells in a specific mouse model.

## Key findings

- Thrombopoietin increases cycling Evi1+ hematopoietic stem cells and speeds up AML development.
- AML from TPO-stimulated HSCs shows higher expression of stem cell genes linked to poor patient outcomes.
- Reducing IL12Rβ2 impairs growth of certain AML cell lines regardless of EVI1 levels.

## 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+ 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 EVI1high KMT2A-rearranged OCI-AML4 cells while reduction of IL12Rβ2 also impairs clonogenic growth of EVI1low 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.

Fusion genes involving KMT2A rearrangements are frequent oncogenic drivers of acute myeloid leukaemia (KMT2A-r AML) but the cell of origin remains unclear. Here, using preclinical models of EVI1 positive KMT2A-r AML the authors investigate the cell of origin and find that the presence of exogenous factors influences AML initiation and the resulting phenotype.