Engraftment characterization of risk-stratified AML patients in NSGS mice

Abstract

Acute myeloid leukemia (AML) is the commonest acute leukemia in adults. Disease heterogeneity is well-documented and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) of risk-stratified AMLs are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is mainly limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We have characterized the engraftment robustness/kinetics in NSGS mice of 28 AML patients grouped according to molecular/cytogenetic classification, and have assessed whether the orthotopic co-administration of patient-matched bone marrow mesenchymal stromal cells (BM-MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85%-94%) of the mice were engrafted in BM independently of the risk group, although HR-AML patients showed engraftment levels significantly superior to those of FR- and IR-AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable overtime. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR-AML patients, fitter leukemia-initiating cells (LICs) in HR- than in FR- or IR-AML samples, and the presence of AML-LICs in the CD34- leukemic fraction, regardless the risk group. Finally, orthotopic co-administration of patient-matched BM-MSCs with AML cells resulted dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.