Deciphering Molecular Heterogeneity in Pediatric AML Using a Cancer Vs. Normal Transcriptomic Approach

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2020 Oct 17

PMID 33069162

Citations 10

Authors

Barbara Depreter

Barbara De Moerloose

Karl Vandepoele

Anne Uyttebroeck

An Van Damme

Eva Terras

Barbara Denys

Laurence Dedeken

Marie-Francoise Dresse

Jutte Van Der Werff Ten Bosch

Mattias Hofmans

Jan Philippe

Tim Lammens

Affiliations

Soon will be listed here.

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.

Citing Articles

Acute myeloid leukemia stem cell signature gene EMP1 is not an eligible therapeutic target.

Van Camp L, Depreter B, De Wilde J, Hofmans M, Van der Linden M, Terras E Pediatr Res. 2024; 97(1):160-168.

PMID: 38879624 DOI: 10.1038/s41390-024-03341-x.

Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.

Plum P, Hess T, Bertrand D, Morgenstern I, Velazquez Camacho O, Jonas C Clin Transl Med. 2024; 14(6):e1723.

PMID: 38877653 PMC: 11178519. DOI: 10.1002/ctm2.1723.

Strategies to overcome low MHC-I expression in paediatric and adult tumours.

Guillaume J, Perzolli A, Boes M Immunother Adv. 2024; 4(1):ltad028.

PMID: 38223409 PMC: 10787372. DOI: 10.1093/immadv/ltad028.

Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells.

Murphy L, Winters A Biomedicines. 2023; 11(12).

PMID: 38137469 PMC: 10741170. DOI: 10.3390/biomedicines11123248.

Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation.

Mougeot J, Beckman M, Hovan A, Hasseus B, Legert K, Johansson J Support Care Cancer. 2023; 31(10):587.

PMID: 37731134 PMC: 10511391. DOI: 10.1007/s00520-023-08044-3.

References

Rasche M, Zimmermann M, Borschel L, Bourquin J, Dworzak M, Klingebiel T . Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia. 2018; 32(10):2167-2177. PMC: 6170392. DOI: 10.1038/s41375-018-0071-7. View

De Moerloose B, Reedijk A, de Bock G, Lammens T, de Haas V, Denys B . Response-guided chemotherapy for pediatric acute myeloid leukemia without hematopoietic stem cell transplantation in first complete remission: Results from protocol DB AML-01. Pediatr Blood Cancer. 2019; 66(5):e27605. DOI: 10.1002/pbc.27605. View

Abrahamsson J, Forestier E, Heldrup J, Jahnukainen K, Jonsson O, Lausen B . Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol. 2010; 29(3):310-5. DOI: 10.1200/JCO.2010.30.6829. View

De Kouchkovsky I, Abdul-Hay M . 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J. 2016; 6(7):e441. PMC: 5030376. DOI: 10.1038/bcj.2016.50. View

Hope K, Jin L, Dick J . Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004; 5(7):738-43. DOI: 10.1038/ni1080. View

Shlush L, Mitchell A, Heisler L, Abelson S, Ng S, Trotman-Grant A . Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017; 547(7661):104-108. DOI: 10.1038/nature22993. View

Witte K, Ahlers J, Schafer I, Andre M, Kerst G, Scheel-Walter H . High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia. Pediatr Hematol Oncol. 2011; 28(2):91-9. DOI: 10.3109/08880018.2010.528171. View

Bachas C, Schuurhuis G, Zwaan C, van den Heuvel-Eibrink M, den Boer M, de Bont E . Gene expression profiles associated with pediatric relapsed AML. PLoS One. 2015; 10(4):e0121730. PMC: 4388534. DOI: 10.1371/journal.pone.0121730. View

Pigazzi M, Masetti R, Bresolin S, Beghin A, Di Meglio A, Gelain S . MLL partner genes drive distinct gene expression profiles and genomic alterations in pediatric acute myeloid leukemia: an AIEOP study. Leukemia. 2011; 25(3):560-3. DOI: 10.1038/leu.2010.316. View

10.

Jo A, Mitani S, Shiba N, Hayashi Y, Hara Y, Takahashi H . High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML. Leukemia. 2015; 29(5):1076-83. DOI: 10.1038/leu.2015.5. View

11.

Andersson A, Ritz C, Lindgren D, Eden P, Lassen C, Heldrup J . Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status. Leukemia. 2007; 21(6):1198-203. DOI: 10.1038/sj.leu.2404688. View

12.

Balgobind B, van den Heuvel-Eibrink M, de Menezes R, Reinhardt D, Hollink I, Arentsen-Peters S . Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. Haematologica. 2010; 96(2):221-30. PMC: 3031689. DOI: 10.3324/haematol.2010.029660. View

13.

Zangrando A, Campo DellOrto M, Te Kronnie G, Basso G . MLL rearrangements in pediatric acute lymphoblastic and myeloblastic leukemias: MLL specific and lineage specific signatures. BMC Med Genomics. 2009; 2:36. PMC: 2709660. DOI: 10.1186/1755-8794-2-36. View

14.

Ross M, Mahfouz R, Onciu M, Liu H, Zhou X, Song G . Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004; 104(12):3679-87. DOI: 10.1182/blood-2004-03-1154. View

15.

Ng S, Mitchell A, Kennedy J, Chen W, McLeod J, Ibrahimova N . A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016; 540(7633):433-437. DOI: 10.1038/nature20598. View

16.

Majeti R, Becker M, Tian Q, Lee T, Yan X, Liu R . Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc Natl Acad Sci U S A. 2009; 106(9):3396-401. PMC: 2642659. DOI: 10.1073/pnas.0900089106. View

17.

Eppert K, Takenaka K, Lechman E, Waldron L, Nilsson B, van Galen P . Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011; 17(9):1086-93. DOI: 10.1038/nm.2415. View

18.

Forsberg E, Passegue E, Prohaska S, Wagers A, Koeva M, Stuart J . Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells. PLoS One. 2010; 5(1):e8785. PMC: 2808351. DOI: 10.1371/journal.pone.0008785. View

19.

Gal H, Amariglio N, Trakhtenbrot L, Jacob-Hirsh J, Margalit O, Avigdor A . Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia. 2006; 20(12):2147-54. DOI: 10.1038/sj.leu.2404401. View

20.

Gentles A, Plevritis S, Majeti R, Alizadeh A . Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA. 2010; 304(24):2706-15. PMC: 4089862. DOI: 10.1001/jama.2010.1862. View