Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention.
UKBB
fusion oncogene
genomic landscape
mouse models
pediatric AML
therapeutic targeting
Journal
Frontiers in pediatrics
ISSN: 2296-2360
Titre abrégé: Front Pediatr
Pays: Switzerland
ID NLM: 101615492
Informations de publication
Date de publication:
2019
2019
Historique:
received:
25
05
2019
accepted:
17
09
2019
entrez:
5
11
2019
pubmed:
5
11
2019
medline:
5
11
2019
Statut:
epublish
Résumé
This review aims to provide an overview of the current knowledge of the genetic lesions driving pediatric acute myeloid leukemia (AML), emerging biological concepts, and strategies for therapeutic intervention. Hereby, we focus on lesions that preferentially or exclusively occur in pediatric patients and molecular markers of aggressive disease with often poor outcome including fusion oncogenes that involve epigenetic regulators like KMT2A, NUP98, or CBFA2T3, respectively. Functional studies were able to demonstrate cooperation with signaling mutations leading to constitutive activation of FLT3 or the RAS signal transduction pathways. We discuss the issues faced to faithfully model pediatric acute leukemia in mice. Emerging experimental evidence suggests that the disease phenotype is dependent on the appropriate expression and activity of the driver fusion oncogenes during a particular window of opportunity during fetal development. We also highlight biochemical studies that deciphered some molecular mechanisms of malignant transformation by KMT2A, NUP98, and CBFA2T3 fusions, which, in some instances, allowed the development of small molecules with potent anti-leukemic activities in preclinical models (e.g., inhibitors of the KMT2A-MENIN interaction). Finally, we discuss other potential therapeutic strategies that not only target driver fusion-controlled signals but also interfere with the transformed cell state either by exploiting the primed apoptosis or vulnerable metabolic states or by increasing tumor cell recognition and elimination by the immune system.
Identifiants
pubmed: 31681706
doi: 10.3389/fped.2019.00401
pmc: PMC6803505
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
401Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 Mercher and Schwaller.
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