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Impact of genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE-93: the effect of TLX3/HOX11L2 gene expression on outcome

¹ Laboratory of Hematology, Hôpital d’Enfants Armand Trousseau APHP
² Department of Pediatric Hematology Oncology
³ Laboratory of Hematology, Hopital Saint Louis, APHP, Paris
⁴ Laboratory of Hematology, Hopital Necker Enfants Malades APHP, Paris
⁵ CEREST-TC, Hôpital Saint Antoine, Université Pierre et Marie Curie-Paris 6
⁶ Department of Pediatrics, Onco-hematology Unit, CHRU, Hôpital Sud, Rennes
⁷ Department of Pediatric Hematology and Oncology, Groupe Hospitalier Pellerin, Bordeaux
⁸ Department of Hematology, Hôpital La Timone, Marseille
⁹ Department of Hematology, Hôpital Saint Louis, APHP, Paris
¹⁰ Department of Oncology and Hematology, Hôpital d’Enfants Vandoeuvres, Les Nancy, France
¹¹ Department of Human Genetics, University of Leuven, Leuven, Belgium

Correspondence: Paola Ballerini, Laboratoire d’Hématologie, Hôpital A. Trousseau, INSERM E0210. E-mail:paola.ballerini{at}trs.aphp.fr:

ABSTRACT

Background: The prognostic value of the ectopic activation of TLX3 gene expression, a major oncogenetic event associated with pediatric T-cell acute lymphoblastic leukemia, is controversial. Likewise, the frequency and the prognostic significance in pediatric T-cell acute lymphoblastic leukemia of the newly characterized NUP214-ABL1 fusion transcript is not yet clear.

Design and Methods: Two hundred children with T-cell acute lymphoblastic leukemia were treated in the French FRALLE-93 study from 1993 to 1999.The expression of TLX3, TLX1 and SILTAL1 genes was analyzed in samples from 92 patients by real-time quantitative reverse transcriptase polymerase chain reaction. Most of these samples were further studied for NUP214-ABL1 and CALM-AF10 fusion transcripts.

Results: The median follow-up was 7.9 years. At 5 years the overall survival (± standard deviation, %) was 62 (± 3%) and leukemia-free survival was 58 (± 3%). Patients with T-cell acute lymphoblastic leukemia positive for TLX3 had a poorer survival compared to those with T-ALL negative for TLX3 (overall survival: 45±11% vs. 57±5%, p=0.049). In multivariate analysis, TLX3 expression was an independent adverse risk factor predicting relapse with a hazard ratio of 2.44 (p=0.017) and an overall survival with a hazard ratio of 3.7 (p=0.001). NUP214-ABL1 was expressed in 16.6% of patients with TLX3-positive T-ALL (3 of 18); all of the patients with this association died before completion of the treatment. SILTAL expression did not significantly affect the prognosis of patients with T-cell acute lymphoblastic leukemia. Only three of 92 patients expressed the TLX1 gene and all three are alive.

Conclusions: TLX3 gene expression is an independent risk factor predicting poor survival in childhood T-cell acute lymphoblastic leukemia. When co-expressed with TLX3, NUP214-ABL1 transcripts may increase the risk of poor survival.

Key words: childhood T-cell acute lymphoblastic leukemia, TLX3/HOX11L2, NUP214-ABL1, SIL-TAL1, outcome.