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

K. Malinowska-Ozdowy, C. Frech, A. Schönegger, C. Eckert, G. Cazzaniga, M. Stanulla, U. Zur Stadt, A. Mecklenbräuker, M. Schuster, D. Kneidinger, A. Von Stackelberg, Franco Locatelli, M. Schrappe, M. A. Horstmann, A. Attarbaschi, C. Bock, G. Mann, O. A. Haas, R. Panzer-Grümayer

Risultato della ricerca: Contributo in rivistaArticolo in rivista

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.
Lingua originaleEnglish
pagine (da-a)1656-1667
Numero di pagine12
RivistaLeukemia
Volume29
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • ALL

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