High CD44 expression and enhanced E-selectin binding identified as biomarkers of chemoresistant leukemic cells in human T-ALL
T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy characterized by increased proliferation and incomplete maturation of T-cell progenitors, for which relapse is often of poor prognosis. To improve patient outcomes, it is critical to understand the chemoresistance mechanisms arising from cell plasticity induced by the bone marrow (BM) microenvironment. Single-cell RNA sequencing of human T-ALL cells from adipocyte-rich and adipocyte-poor BM revealed a distinct leukemic cell population defined by quiescence and high CD44 expression (Ki67<sup>neg/low</sup>CD44<sup>high</sup>). During in vivo treatment, these cells evaded chemotherapy, and were further called Chemotherapy-resistant Leukemic Cells (CLCs). Patient sample analysis revealed Ki67<sup>neg/low</sup>CD44<sup>high</sup> CLCs at diagnosis and during relapse, with each displaying a specific transcriptomic signature. Interestingly, CD44<sup>high</sup> expression in T-ALL Ki67<sup>neg/low</sup> CLCs was associated with E-selectin binding. Analysis of 39 human T-ALL samples revealed significantly enhanced E-selectin binding activity in relapse/refractory samples compared with drug-sensitive samples. These characteristics of chemoresistant T-ALL CLCs provide key insights for prognostic stratification and novel therapeutic options.
Authors
- Stéphane J.C. Mancini (ORCID: https://orcid.org/0000-0001-9255-4606)
- Irina Naguibneva (ORCID: https://orcid.org/0000-0001-9566-6152)
- Benjamin Uzan (ORCID: https://orcid.org/0000-0001-6323-5737)
- Léa Bellenger (ORCID: https://orcid.org/0000-0002-5332-7870)
- Laurent Renou (ORCID: https://orcid.org/0009-0005-7793-8544)
- Arnaud Petit (ORCID: https://orcid.org/0000-0001-8363-1622)
- Hélène Lapillonne (ORCID: https://orcid.org/0000-0002-6900-8313)
- Paola Ballerini (ORCID: https://orcid.org/0009-0005-4844-7762)
- Françoise Pflumio (ORCID: https://orcid.org/0000-0001-8995-596X)
- Jean‐François Peyron (ORCID: https://orcid.org/0000-0001-6113-916X)
- Julien Calvo (ORCID: https://orcid.org/0000-0003-1316-4306)
- Tony Marchand (ORCID: https://orcid.org/0000-0003-4932-2169)
- Christophe Antoniewski (ORCID: https://orcid.org/0000-0001-7709-2116)
- Anthony Kypraios
- Baptiste Gaillard
- Florian Gilain
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Côte d'Azur (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Sorbonne Université (FR)
- Hôpital Armand-Trousseau (FR)
- Acute Leukemia French Association (FR)
- La Ligue Contre le Cancer (FR)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre Méditerranéen de Médecine Moléculaire (FR)
- CEA Paris-Saclay (FR)
- Centre de Recherche Saint-Antoine (FR)
- Institut Français de Bioinformatique (FR)
- Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques (FR)
- Institut de Radiobiologie Cellulaire et Moléculaire (FR)
- Centre Hospitalier Universitaire de Rennes (FR)
- Microenvironment and B-cells: Immunopathology, Cell, Differentiation and Cancer (FR)
- Université de Rennes (FR)
Publication Details
- Journal
- Leukemia
- Published
- 2024-11-23
- DOI
- https://doi.org/10.1038/s41375-024-02473-7
- Citations
- 7
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 3.80
Funders
- Association Laurette Fugain
- Institut National de la Santé et de la Recherche Médicale