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Our understanding of the hierarchical structure of acute leukemia has yet to be fully translated into therapeutic approaches. Indeed, chemotherapy still has to take into account the possibility that leukemia-initiating cells may have a distinct chemosensitivity profile compared to the bulk of the tumor, and therefore are spared by the current treatment, causing the relapse of the disease. Therefore, the identification of the cell-of-origin of leukemia remains a longstanding question and an exciting challenge in cancer research of the last few decades. With a particular focus on acute lymphoblastic leukemia, we present in this review the previous and current concepts exploring the phenotypic, genetic and functional heterogeneity in patients. We also discuss the benefits of using engineered mouse models to explore the early steps of leukemia development and to identify the biological mechanisms driving the emergence of leukemia-initiating cells. Finally, we describe the major prospects for the discovery of new therapeutic strategies that specifically target their aberrant stem cell-like functions.
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http://dx.doi.org/10.3390/cancers13215511 | DOI Listing |
Nat Immunol
September 2025
Immune System Development and Function Unit. Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Targeted immunotherapy for T cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T cell progenitors, is an urgent unmet need, especially for relapsed/refractory disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-T cell receptor (pre-TCR), a surface receptor essential for T cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL.
View Article and Find Full Text PDFCell Rep
August 2025
Department of Pediatrics, Aflac Cancer & Blood Disorders Center, Winship Cancer Institute, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA. Electronic address:
Juvenile myelomonocytic leukemia (JMML) originates from mutated hematopoietic stem cells. The mechanism by which mutant stem cells are sustained, leading to leukemia development, remains elusive. By comprehensively examining transcriptomic profiles, cell compositions, developmental trajectories, and cell-cell interactions across various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML, we find that Ptpn11 mutant stem cells exhibit de novo activation of the myeloid transcriptional program and markedly increased expression of innate immunity-associated antimicrobial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8.
View Article and Find Full Text PDFJ Immunother Cancer
July 2025
Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
Background: While chimeric antigen receptor (CAR)-T cell therapy exhibits a robust therapeutic efficacy against B-cell malignancies and multiple myeloma, its efficacy and safety have not been established for acute myeloid leukemia (AML) and solid tumors due to the paucity of established target antigens. Some AML and solid tumor cells express tumor necrosis factor (TNF), which is initially expressed on the cell surface prior to shedding.
Methods: In this study, we obtained monoclonal antibodies against the N-terminal fragment of TNF (TNF-NTF) that remains on the cell surface after shedding.
Mol Cells
September 2025
Binzhou Medical University, Yantai Hospital of Traditional Chinese Medicine, Yantai, 264003, China. Electronic address:
CD84, a member of the signaling lymphocyte activation molecule immunoglobulin superfamily, has been identified as playing a significant role in regulating various immune cell activities. However, its intrinsic role in cancer cells remains largely unknown. We aim to explore the direct role of CD84 in acute myeloid leukemia (AML) progression and to clarify the underlying molecular mechanisms involved in nonhomologous end-joining (NHEJ) repair.
View Article and Find Full Text PDFJ Immunother Cancer
June 2025
Department of Immunology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure to treat hematopoietic disorders. Current bone marrow conditioning protocols create space for healthy donor stem cells by employing irradiation and/or chemotherapy, but carry severe toxicities, resulting in significant morbidity, mortality and substantial long-term complications. To develop a low-toxicity solution, we generated a bi-specific T-cell engager (BTCE) that targets CD117, an abundantly expressed receptor on hematopoietic stem and progenitor cells (HSPC) and leukemia-initiating cells (LICs).
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