Nidogen-1, a Player in KMT2A-Rearranged Pediatric Acute Myeloid Leukemia

  • Int J Mol Sci. 2025 Mar 26;26(7):3011. doi: 10.3390/ijms26073011.
Jolien Vanhooren  1  2  3 ,  Larissa Deneweth  1  2  3 ,  Luca Pagliaro  4  5  6 ,  Zhiyao Ren  1  2  3 ,  Mariateresa Giaimo  4  5  6 ,  Rafaella Zamponi  4  5  6 ,  Giovanni Roti  4  5  6 ,  Barbara Depreter  7  8 ,  Mattias Hofmans  3  9  10 ,  Barbara De Moerloose  1  2  3 ,  Tim Lammens  1  2  3
Affiliations
  • 1. Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium.
  • 2. Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium.
  • 3. Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium.
  • 4. Translational Hematology and Chemogenomics (THEC), University of Parma, 43121 Parma, Italy.
  • 5. Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy.
  • 6. Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, 43121 Parma, Italy.
  • 7. Department of Laboratory Medicine, AZ Delta General Hospital, 8800 Roeselare, Belgium.
  • 8. Department of Haematology, Vrije Universiteit Brussel (VUB), 1000 Brussels, Belgium.
  • 9. Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium.
  • 10. Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
PMID: 40243655 DOI: 10.3390/ijms26073011
Abstract

Despite advances in outcome, one third of children with acute myeloid leukemia (AML) relapse, and less than half will achieve long-term survival. Relapse in AML has been shown to be driven in part by leukemic stem cells (LSCs), highlighting the unmet medical need to better characterize and target this therapy-resistant cell population. Micro-array profiling of pediatric AML subpopulations (LSCs and leukemic myeloblasts) and their healthy counterparts revealed nidogen-1 (NID1) as expressed in both leukemic subpopulations while absent in the hematopoietic stem cell. Using the TARGET dataset including pediatric AML patients (n = 1025), NID1 expression showed a correlation with worse event-free survival and KMT2A rearrangements. Drug response profiling of a NID1 knockdown model demonstrated differential sensitivity to HSP90 inhibition. RNA Sequencing and gene set enrichment analysis between NID1high and NID1low phenotypes showed involvement of NID1 in mitochondrial metabolic pathways known to be enriched in LSCs. Altogether, this study highlights NID1 as a novel oncogene associated with worse EFS and metabolic LSC phenotype in AML. NID1 could serve as a biomarker and aid in further mapping LSCs to establish therapeutic strategies tackling the high relapse rates in pediatric AML.

Keywords
AML; leukemic stem cell; nidogen-1.
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