Open Access Green as soon as Postprint is submitted to ZB.
Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.
Blood 122, 1761-1769 (2013)
The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors, RUNX1 and CBFB, respectively, are found in 15-20% of adult de novo AML cases and are associated with a favourable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the ATP-binding domain (TKD1) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5/84, 6%; 1/36, 3%). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD, confers resistance to the FLT3 PTK inhibitors PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend towards a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in CBF leukemias and suggests a defined subgroup of CBF leukemias. Registered at www.clinicaltrials.gov: AMLCG-1999 trial (NCT00266136).
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid-leukemia ; Acute Myelogenous Leukemia ; Kinase Domain ; Juxtamembrane Domain ; Aml ; Resistance ; Pathway ; Gene ; Cbfb-myh11 ; Prediction
ISSN (print) / ISBN 0006-4971
Quellenangaben Volume: 122, Issue: 10, Pages: 1761-1769
Publisher American Society of Hematology
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)