Barbara Depreter1, Barbara De Moerloose2,3,4, Karl Vandepoele3,5, Anne Uyttebroeck6, An Van Damme7, Eva Terras4, Barbara Denys5, Laurence Dedeken8, Marie-Françoise Dresse9, Jutte Van der Werff Ten Bosch10, Mattias Hofmans2,3, Jan Philippé3,5,11, Tim Lammens2,3,4. 1. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. barbara.depreter@uzbrussel.be. 2. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. 3. Cancer Research Institute Ghent, Ghent, Belgium. 4. Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium. 5. Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium. 6. Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium. 7. Department of Pediatric Hematology Oncology, University Hospital Saint-Luc, Brussels, Belgium. 8. Department of Pediatric Hematology Oncology, Queen Fabiola Children's University Hospital, Brussels, Belgium. 9. Department of Pediatric Hematology Oncology, University Hospital Liège, Liège, Belgium. 10. Department of Pediatric Hematology Oncology, University Hospital Brussel, Brussels, Belgium. 11. Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
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.
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.
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Authors: Liran I Shlush; Amanda Mitchell; Lawrence Heisler; Sagi Abelson; Stanley W K Ng; Aaron Trotman-Grant; Jessie J F Medeiros; Abilasha Rao-Bhatia; Ivana Jaciw-Zurakowsky; Rene Marke; Jessica L McLeod; Monica Doedens; Gary Bader; Veronique Voisin; ChangJiang Xu; John D McPherson; Thomas J Hudson; Jean C Y Wang; Mark D Minden; John E Dick Journal: Nature Date: 2017-06-28 Impact factor: 49.962
Authors: Costa Bachas; Gerrit Jan Schuurhuis; C Michel Zwaan; Marry M van den Heuvel-Eibrink; Monique L den Boer; Eveline S J M de Bont; Zinia J Kwidama; Dirk Reinhardt; Ursula Creutzig; Valérie de Haas; Gertjan J L Kaspers; Jacqueline Cloos Journal: PLoS One Date: 2015-04-07 Impact factor: 3.240
Authors: Jolien Vanhooren; Laurens Van Camp; Barbara Depreter; Martijn de Jong; Anne Uyttebroeck; An Van Damme; Laurence Dedeken; Marie-Françoise Dresse; Jutte van der Werff Ten Bosch; Mattias Hofmans; Jan Philippé; Barbara De Moerloose; Tim Lammens Journal: Cancers (Basel) Date: 2022-04-22 Impact factor: 6.639