TY  - JOUR
A1  - Neumann, Martin
A1  - Coskun, Ebru
A1  - Fransecky, Lars
A1  - Mochmann, Liliana H.
A1  - Bartram, Isabelle
A1  - Sartangi, Nasrin Farhadi
A1  - Heesch, Sandra
A1  - Gökbuget, Nicola
A1  - Schwartz, Stefan
A1  - Brandts, Christian Hubertus
A1  - Schlee, Cornelia
A1  - Haas, Rainer
A1  - Dührsen, Ulrich
A1  - Griesshammer, Martin
A1  - Döhner, Hartmut
A1  - Ehninger, Gerhard
A1  - Burmeister, Thomas
A1  - Blau, Olga
A1  - Thiel, Eckhard
A1  - Hoelzer, Dieter
A1  - Hofmann, Wolf-Karsten
A1  - Baldus, Claudia
T1  - FLT3 mutations in Early T-Cell Precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors
T2  - PLoS One
N2  - Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup.
Y1  - 2013
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/28705
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-287052
SN  - 1932-6203
N1  - Copyright: © 2013 Neumann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
VL  - 8
IS  - 1: e53190
PB  - PLoS
CY  - Lawrence, Kan.
ER  -