Toggle Main Menu Toggle Search

Open Access padlockePrints

Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition

Lookup NU author(s): Professor Julie Irving, Elizabeth Matheson, Dr Helen Blair, Marian Case, Isabella Swidenbank, Dr Frida Ponthan, Professor James Allan, Professor Christine Harrison, Professor Josef Vormoor

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

For most children who relapse with acute lymphoblastic leukemia (ALL), the prognosis is poor, and there is a need for novel therapies to improve outcome. We screened samples from children with B-lineage ALL entered into the ALL-REZ BFM 2002 clinical trial (www.clinicaltrials.gov, #NCT00114348) for somatic mutations activating the Ras pathway (KRAS, NRAS, FLT3, and PTPN11) and showed mutation to be highly prevalent (76 from 206). Clinically, they were associated with high-risk features including early relapse, central nervous system (CNS) involvement, and specifically for NRAS/KRAS mutations, chemoresistance. KRAS mutations were associated with a reduced overall survival. Mutation screening of the matched diagnostic samples found many to be wild type (WT); however, by using more sensitive allelic-specific assays, low-level mutated subpopulations were found in many cases, suggesting that they survived up-front therapy and subsequently emerged at relapse. Preclinical evaluation of the mitogen-activated protein kinase kinase 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) showed significant differential sensitivity in Ras pathway-mutated ALL compared with WT cells both in vitro and in an orthotopic xenograft model engrafted with primary ALL; in the latter, reduced RAS-mutated CNS leukemia. Given these data, clinical evaluation of selumetinib may be warranted for Ras pathway-mutated relapsed ALL.


Publication metadata

Author(s): Irving J, Matheson E, Minto L, Blair H, Case M, Halsey C, Swidenbank I, Ponthan F, Kirschner-Schwabe R, Groeneveld-Krentz S, Hof J, Allan J, Harrison C, Vormoor J, von Stackelberg A, Eckert C

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2014

Volume: 124

Issue: 23

Pages: 3420-3430

Print publication date: 27/11/2014

Acceptance date: 26/08/2014

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: http://dx.doi.org/10.1182/blood-2014-04-531871

DOI: 10.1182/blood-2014-04-531871


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share