Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs.
TLX1 is a homeodomain transcription factor generally associated with a favorable outcome in T-cell acute lymphoblastic leukemia (T-ALL). However, the molecular mechanisms of TLX1 deregulation remain unclear and various transcript levels in the absence of 10q24 abnormalities have been reported. A reproducible and accurate delineation of TLX1(+) T-ALL will be necessary for proper therapeutic stratification. We have studied 264 unselected T-ALLs (171 adults and 93 children) and show that T-ALLs expressing high levels of TLX1 (n = 35, 13%), defined as a real-time quantitative polymerase chain reaction (RQ-PCR) level of TLX1 greater than 1.00 ABL, form a homogeneous oncogenic group, based on their uniform stage of maturation arrest and oncogenetic and transcriptional profiles. Furthermore, TLX1-high T-ALLs harbor molecular TLX1 locus abnormalities in the majority (31/33), a proportion largely underestimated by standard karyotypic screening. T-ALLs expressing TLX1 at lower levels (n = 57, 22%) do not share these characteristics. Prognostic analysis within the adult LALA94 and GRAALL03 prospective protocols demonstrate a better event-free survival (P = .035) and a marked trend for longer overall survival (P = .059) for TLX1-high T-ALLs, while the expression of lower levels of TLX1 does not impact on prognosis. We propose that TLX1(+) T-ALLs be defined as cases expressing TLX1/ABL ratios greater than 1 and/or demonstrating TLX1 rearrangement. Therapeutic modification should be considered for those patients.
Bergeron
Julie
J
The Université Paris V René Descartes, Institut National de la Santé et de la Recherche Médicale (INSERM) EMI0210 and Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Necker-Enfants-Malades, Paris, France.
Clappier
Emmanuelle
E
Radford
Isabelle
I
Buzyn
Agnès
A
Millien
Corinne
C
Soler
Gwendoline
G
Ballerini
Paola
P
Thomas
Xavier
X
Soulier
Jean
J
Dombret
Hervé
H
Macintyre
Elizabeth A
EA
Asnafi
Vahid
V
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007125:Immunogenetics; D007621:Karyotyping; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015996:Survival Rate; D014158:Transcription, Genetic / Q000235:genetics
D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C071250:TLX1 protein, human