Engraftment characterization of risk-stratified AML in NSGS mice

Rafael Díaz de La Guardia (1, 2) , Talía Velasco-Hernandez (1) , Francisco Gutiérrez-Agüera (1) , Heleia Roca-Ho (1) , Oscar Molina (1) , Cesar Nombela-Arrieta (3) , Alex Bataller (1) , Jose Luis Fuster (4) , Eduardo Anguita (5) , Susana Vives (6, 1) , Lurdes Zamora (6, 1) , Josep Nomdedeu (7, 1) , María Teresa Gómez-Casares (8) , Manuel Ramírez-Orellana (9) , Helene Lapillonne (10, 11) , Verónica Ramos-Mejia (2) , Juan Carlos Rodríguez-Manzaneque (2) , Clara Bueno (12, 1) , Belen Lopez-Millan (2, 1) , Pablo Menéndez (11, 10, 13)

1 University of Barcelona
2 UGR - Universidad de Granada = University of Granada
3 University hospital of Zurich [Zurich]
4 Hospital Clínico Universitario Virgen de la Arrixaca = University Hospital Virgen de la Arrixaca [Murcia]
5 IdISSC - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain]
6 IGTP - Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute
7 Hospital de la Santa Creu i Sant Pau
8 ULPGC - Universidad de las Palmas de Gran Canaria
9 Hospital del Niño Jesus, San Miguel de Tucumán
10 CHU Trousseau [APHP]
11 CRSA - Centre de Recherche Saint-Antoine
12 CIBERO - Centro de Investigación Biomedica en Red de Oncologia [Pamplona, Spain]
13 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies

Key Points - PDXs from risk-stratified AML samples are crucial for studying AML biology and testing novel therapeutics. - We characterize human AML engraftment in NSGS mice, offering a valuable platform for in vivo testing of targeted therapies. Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment robustness/kinetics of 28 AML patient samples grouped according to molecular/cytogenetic classification and assessed whether the orthotopic coadministration 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 bone marrow (BM) independently of the risk group, although HR AML patients showed engraftment levels that were significantly superior to those of FR or IR AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable over time. 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 AML samples, and the presence of AML LICs in the CD34− leukemic fraction, regardless of the risk group. Finally, orthotopic coadministration of patient-matched BM MSCs and AML cells was 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

Mots clés: Hematopoiesis and Stem Cells; Myeloid Neoplasia

Domaines: Médecine humaine et pathologie

Rafael Díaz de La Guardia, Talía Velasco-Hernandez, Francisco Gutiérrez-Agüera, Heleia Roca-Ho, Oscar Molina, et al.. Engraftment characterization of risk-stratified AML in NSGS mice. Blood Advances, 2021, 5 (23), pp.4842-4854. ⟨10.1182/bloodadvances.2020003958⟩. ⟨hal-03528534⟩