High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.

KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia / Malinowska-Ozdowy, K.; Frech, C.; Schonegger, A.; Eckert, C.; Cazzaniga, G.; Stanulla, M.; Zur Stadt, U.; Mecklenbrauker, A.; Schuster, M.; Kneidinger, D.; Von Stackelberg, A.; Locatelli, F.; Schrappe, M.; Horstmann, M. A.; Attarbaschi, A.; Bock, C.; Mann, G.; Haas, O. A.; Panzer-Grumayer, R.. - In: LEUKEMIA. - ISSN 0887-6924. - 29:8(2015), pp. 1656-1667. [10.1038/leu.2015.107]

KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia

Locatelli F.;
2015

Abstract

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.
2015
minimal residual disease; ras; cancer; children; landscape; discovery; origins; clones
01 Pubblicazione su rivista::01a Articolo in rivista
KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia / Malinowska-Ozdowy, K.; Frech, C.; Schonegger, A.; Eckert, C.; Cazzaniga, G.; Stanulla, M.; Zur Stadt, U.; Mecklenbrauker, A.; Schuster, M.; Kneidinger, D.; Von Stackelberg, A.; Locatelli, F.; Schrappe, M.; Horstmann, M. A.; Attarbaschi, A.; Bock, C.; Mann, G.; Haas, O. A.; Panzer-Grumayer, R.. - In: LEUKEMIA. - ISSN 0887-6924. - 29:8(2015), pp. 1656-1667. [10.1038/leu.2015.107]
File allegati a questo prodotto
File Dimensione Formato  
Malinowska-Ozdowy_KRAS and CREBBP mutations_2015.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 1.65 MB
Formato Adobe PDF
1.65 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1482277
Citazioni
  • ???jsp.display-item.citation.pmc??? 53
  • Scopus 87
  • ???jsp.display-item.citation.isi??? 84
social impact