TY - JOUR
T1 - Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome
AU - Châtel-Soulet, Hugues-Étienne
AU - Juge, Sabine
AU - Pereira, Ana Luisa
AU - Seguin, Jonathan
AU - El Taher, Athimed
AU - Valigi, Federica
AU - Jevtic, Zivojin
AU - Sivalingam, Rathick
AU - Bagger, Frederik Otzen
AU - Büschl, Paul
AU - Almosailleakh, Marwa
AU - Tzankov, Alexander
AU - Tong, Wei
AU - Kurokawa, Mineo
AU - Nombela Arrieta, César
AU - Schwaller, Juerg
N1 - © 2025. The Author(s).
PY - 2025/12/19
Y1 - 2025/12/19
N2 - 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.
AB - 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.
KW - Animals
KW - Disease Models, Animal
KW - HL-60 Cells
KW - Hematopoietic Stem Cells/metabolism
KW - Histone-Lysine N-Methyltransferase/genetics
KW - Humans
KW - Leukemia, Myeloid, Acute/genetics
KW - MDS1 and EVI1 Complex Locus Protein/genetics
KW - Mice
KW - Myeloid-Lymphoid Leukemia Protein/genetics
KW - Oncogene Proteins, Fusion/genetics
KW - Thrombopoietin/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=105028526519&partnerID=8YFLogxK
U2 - 10.1038/s41467-025-67611-w
DO - 10.1038/s41467-025-67611-w
M3 - Journal article
C2 - 41419472
SN - 2041-1722
VL - 17
SP - 892
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 892
ER -