Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRβ-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique

Abstract

Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRb) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRb-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRb-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRb-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRb-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRb-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRb-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.

Hox genes in hematopoiesis and leukemogenesis

“…Gene expression analysis showed that the whole HOXA gene cluster was dramatically dysregulated in T-cell acute lymphocytic leukemia samples harboring the TCRb-HOXA rearrangement (Speleman et al, 2005;Cauwelier et al, 2007). HOXA genes were also found to be upregulated in MLL and CALM-AF10-related T-cell acute lymphoblastic leukemias cases, strongly suggesting that HOXA genes are oncogenic in these leukemias (Soulier et al, 2005).…”

In vitro validation of -secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia

“…The detection of mutated NOTCH1 sequences encoding the heterodimezation domain and PEST domains was described previously. 22 This study was approved by the Ethical Committee of the Medical Faculty of the University of Leuven. Informed consent was obtained from all subjects.…”

The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia

“…Although most HOXA genes were highly expressed in LOUCY, in the patient with AUL and in the SET-NUP214 ϩ patients with T-ALL, expression of HOXA11 and HOXA13 was virtually absent. In addition, the expression of the short HOXA10 isoform, HOXA10B, which previously has been exclusively associated with patients with inv(7)(p15q34) T-ALL, 8,20 was also highly expressed in the SET-NUP214 ϩ patients ( Figure 4C).From the expression microarray data, the most significant and differentially expressed probesets were calculated for the entire HOXA cluster. A total of 20 significant and differentially expressed probesets with a FDR rate lower than 5% were obtained for this cluster ( Figure 4D).…”

“…This cluster includes patients with CALM-AF10 8,18 or MLL rearrangements, 8,19 or patients with an inversion on chromosome 7 due to the rearrangement of the T-cell receptor-beta (TCR␤) locus into the HOXA cluster. 8,10 Elevated HOXA gene expression levels have also been reported in the absence of these genetic aberrations, 8,20 suggesting that alternative mechanisms of HOXA activation may exist in T-ALL.Previously, we have studied the incidence and prognostic relevance of recurrent molecular cytogenetic abnormalities for pediatric T-ALL. 21 Within our cohort, about half of the patients Submitted September 10, 2007; accepted February 12, 2008.…”