Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia

Matteo Maria Naldini, Gabriele Casirati, Matteo Barcella, Paola Maria Vittoria Rancoita, Andrea Cosentino, Carolina Caserta, Francesca Pavesi, Erika Zonari, Giacomo Desantis, Diego Gilioli, Matteo Giovanni Carrabba, Luca Vago, Massimo Bernardi, Raffaella Micco, Clelia Serio, Ivan Merelli, Monica Volpin, Eugenio Montini, Fabio Ciceri and Bernhard Gentner ()
Additional contact information
Matteo Maria Naldini: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Gabriele Casirati: Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital
Matteo Barcella: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Paola Maria Vittoria Rancoita: Vita-Salute San Raffaele University
Andrea Cosentino: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Carolina Caserta: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Francesca Pavesi: Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital
Erika Zonari: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Giacomo Desantis: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Diego Gilioli: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Matteo Giovanni Carrabba: Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital
Luca Vago: Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital
Massimo Bernardi: Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital
Raffaella Micco: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Clelia Serio: Vita-Salute San Raffaele University
Ivan Merelli: National Research Council, Institute for Biomedical Technologies
Monica Volpin: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Eugenio Montini: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
Fabio Ciceri: Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital
Bernhard Gentner: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts.

Date: 2023
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DOI: 10.1038/s41467-023-36969-0

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