A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias

Abstract

Chromosomal translocations with breakpoints in T-cell receptor (TCR) genes are recurrent in T-cell malignancies. These translocations involve the TCRad gene (14q11), the TCRb gene (7q34) and to a lesser extent the TCRc gene at chromosomal band 7p14 and juxtapose T-cell oncogenes next to TCR regulatory sequences leading to deregulated expression of those oncogenes. Here, we describe a new recurrent chromosomal inversion of chromosome 7, inv(7)(p15q34), in a subset of patients with T-cell acute lymphoblastic leukemia characterized by CD2 negative and CD4 positive, CD8 negative blasts. This rearrangement juxtaposes the distal part of the HOXA gene cluster on 7p15 to the TCRb locus on 7q34. Real time quantitative PCR analysis for all HOXA genes revealed high levels of HOXA10 and HOXA11 expression in all inv (7) positive cases. This is the first report of a recurrent chromosome rearrangement targeting the HOXA gene cluster in T-cell malignancies resulting in deregulated HOXA gene expression (particularly HOXA10 and HOXA11) and is in keeping with a previous report suggesting HOXA deregulation in MLL-rearranged T-and B cell lymphoblastic leukemia as the key factor in leukaemic transformation. Finally, our observation also supports the previous suggested role of HOXA10 and HOXA11 in normal thymocyte development.

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).…”

The role of CALM–AF10 gene fusion in acute leukemia

“…59 Chromosomal translocations also lead to ectopic expression of HOXA cluster genes by juxtaposition of TCRA regulatory elements with HOXA coding sequences in some patients with T-cell ALL. 60,61 In addition to these translocations, which directly lead to overexpression of HOX genes, a number of recent studies have demonstrated that chromosome translocations, which result in MLL fusions, lead to unscheduled expression of HOX genes in both AML and T-cell ALL patients. 62 In addition to these studies showing HOX gene dysregulation resulting from chromosomal translocations, global gene Role of CALM-AF10 gene fusion in acute leukemia D Caudell and PD Aplan expression profiling has identified HOX genes as being consistently overexpressed in AML.…”

Chronic myeloproliferative disorders: a tyrosine kinase tale

“…However, we may also not forget that cryptic chromosomal translocations and inversions could also still be undiscovered, as was illustrated by the recent identification of a cryptic t(9;14) resulting in an EML1-ABL1 fusion in T-ALL, 38 and a cryptic inv(7) affecting the HOXA cluster in T-ALL. 39 Finally, point mutations and other subtle nucleotide changes can only be identified by sequencing analysis. Large-scale sequence analysis of all kinase genes has already resulted in the identification of novel tyrosine kinase mutations, including ERBB2 in lung cancer and JAK2 in CMPDs.…”