Clonal genetic aberrations in tumour cells provide critical information for the development of new diagnostic and therapeutic strategies for patients. In paediatric T-cell acute lymphoblastic leukaemia (T-ALL) chromosomal translocations are present in 30-35% of cases. HOX11 and the closely related HOX11L2 genes play a key role in T-ALL. HOX11 is aberrantly activated by either of the two chromosomal translocations, t(7;10) and t(10;14). In this study, HOX11 expression levels were measured by real-time quantitative reverse-transcriptase polymerase chain reaction. We show that leukaemic blasts from 15/76 (19.7%) paediatric T-ALL patients expressed the HOX11 gene at high level and 22/76 (28.9%) at low level, yet the reported frequency for chromosomal rearrangement of 10q24 is 4-7%. Direct cytogenetic analysis revealed that only 2/16 specimens that showed HOX11 expression exhibited abnormalities at 10q24. These results confirm and extend our previously published findings, and implicate mechanisms other than gross chromosomal translocations for the deregulation of HOX11. Analysis of clinical outcome for the whole study group showed a trend for better outcome for patients with leukaemic blasts expressing HOX11 at high level. A statistically significant difference in clinical outcome was found in a subgroup of 20 patients treated for high-risk disease on CCG-1901 from the Children's Cancer Group, where HOX11 expression in leukaemic blasts conferred a prognostic advantage (P ¼ 0.01).
The genes at the INK4A/ARF locus at 9p21 are frequently involved in human cancer. Virtually all p16 INK4A exon 2 (henceforth called p16) inactivation in pediatric acute lymphoblastic leukemia (ALL) occurs by gene deletion. The results of this study illustrate that real-time quantitative polymerase chain reaction is capable of detecting gene deletion in primary patient specimens with a precision not previously achieved by conventional methods. Importantly, this assay includes the detection of hemizygous deletions. The study revealed, strikingly, that the risk ratio for relapse for hemizygous deletion compared with no deletion was 6.558 (P ؍ .00687) and for homozygous deletion was 11.558 (P ؍ .000539). These results confirm and extend the authors' previous findings that homozygous deletion of p16 in pediatric ALL patients is an independent prognostic indicator of outcome from therapy. (Blood. 2001;97:572-574)
Despite considerable work on the epigenetic control of tumor suppressor genes, little is known about the potential role of promoter CpG demethylation in the activation of oncogenes in lymphoid tumors. The HOX11 proto‐oncogene is frequently activated in T‐cell acute lymphoblastic leukemia (T‐ALL). HOX11 activation can occur in the absence of translocation of the gene to the T‐cell receptor locus (Salvati et al., 1995), implying that activation mechanisms must be involved other than the juxtaposition of the gene to adjacent enhancing sequences. We tested whether the methylation status of the proximal promoter was correlated with expression status in T‐ALL and found that, in all cases, expression of HOX11 in T‐ALL was associated with extensive demethylation of the proximal HOX11 promoter, regardless of whether or not translocation was involved. In contrast, cells that did not express HOX11 showed a more methylated pattern of CpG residues in the proximal promoter. Methylation of this sequence in vitro was sufficient to silence the proximal promoter. We propose a model in which the selection of leukemia clones via a pathway involving HOX11 expression requires the demethylation of its promoter as a prerequisite for additional gene activation mechanisms. © 2000 Wiley‐Liss, Inc.
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