inv(16) and NPM1mut AMLs engraft human cytokine knock-in mice

Favorable-risk human acute myeloid leukemia (AML) engrafts poorly in currently mostly used immuno-deficient mice, possibly due to insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated NPM1 mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (M-CSF, IL-3, GM-CSF, Thrombopoietin) were knocked into their respective mouse loci. NPM1 mut AML engrafted with higher efficacy in cytokine knock-in mice and showed a trend towards higher bone marrow engraftment levels in comparison to NSG mice. Inv(16) AML engrafted with high efficacy and was serially transplantable in cytokine knock-in mice, but in contrast exhibited virtually no engraftment in NSG mice. Selected use of cytokine knock-in mice revealed that human macrophage colony-stimulating factor (M-CSF) was required for inv(16) AML engraftment. Subsequent transcriptome profiling in an independent AML patient study cohort demonstrated high expression of M-CSF receptor and enrichment of M-CSF inducible genes in inv(16) AML cases. This study thus provides a first xeno-transplantation mouse model for and informs on disease biology of inv(16) AML.