1. Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach
- Author
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Marie-Françoise Dresse, An Van Damme, Barbara Depreter, Tim Lammens, Barbara De Moerloose, Barbara Denys, Mattias Hofmans, Jutte van der Werff ten Bosch, Anne Uyttebroeck, Eva Terras, Karl Vandepoele, Jan Philippé, Laurence Dedeken, Clinical sciences, Clinical Biology, Growth and Development, Pediatrics, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique
- Subjects
Male ,Adolescent ,medicine.medical_treatment ,medicine.disease_cause ,Targeted therapy ,Transcriptome ,Genetic Heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,030225 pediatrics ,Humans ,Medicine ,Pediatrics, Perinatology, and Child Health ,molecular heterogeneity ,Child ,pediatric AML ,Cancer ,business.industry ,hematology ,Infant ,Immune dysregulation ,medicine.disease ,normal transcriptomic approach ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Real-time polymerase chain reaction ,Case-Control Studies ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,oncology ,Cancer research ,Female ,Stem cell ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Background Still 30–40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers. Methods Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis. Results Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast. Conclusion Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML. Impact Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.
- Published
- 2021