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

Author

Listed:
  • Matteo Maria Naldini

    (San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
    Vita-Salute San Raffaele University)

  • 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
    National Research Council, Institute for Biomedical Technologies)

  • 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
    Vita-Salute San Raffaele University)

  • Carolina Caserta

    (San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute
    Vita-Salute San Raffaele University)

  • 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
    Vita-Salute San Raffaele University)

  • 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
    Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital
    University of Lausanne (UNIL) and Lausanne University Hospital (CHUV))

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.

Suggested Citation

  • Matteo Maria Naldini & Gabriele Casirati & Matteo Barcella & Paola Maria Vittoria Rancoita & Andrea Cosentino & Carolina Caserta & Francesca Pavesi & Erika Zonari & Giacomo Desantis & Diego Gilioli & , 2023. "Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36969-0
    DOI: 10.1038/s41467-023-36969-0
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