HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL)

Abstract

Using a combination of molecular cytogenetic and large-scale expression analysis in human T-cell acute lymphoblastic leukemias (T-ALLs), we identified and characterized a new recurrent chromosomal translocation, targeting the major homeobox gene cluster HOXA and the TCRB locus. Real-time quantitative polymerase chain reaction (RQ-PCR) analysis showed that the expression of the whole HOXA gene cluster was dramatically dysregulated in the HOXA-rearranged cases, and also in MLL and CALM-AF10 -related T-ALL cases, strongly suggesting that HOXA genes are oncogenic in these leukemias. Inclusion of HOXA-translocated cases in a general molecular portrait of 92 T-ALLs based on large-scale expression analysis shows that this rearrangement defines a new homogeneous subgroup, which shares common biologic networks with the TLX1-and TLX3-related cases. Because T-ALLs derive from T-cell progenitors, expression profiles of the distinct T-ALL subgroups were analyzed with respect to those of normal human thymic subpopulations. Inappropriate use or perturbation of specific molecular networks involved in thymic differentiation was detected. Moreover, we found a significant association between T-ALL oncogenic subgroups and ectopic expression of a limited set of genes, including several developmental genes, namely HOXA, TLX1, TLX3, NKX3-1, SIX6, and TFAP2C. These data strongly support the view that the abnormal expression of developmental genes, including the prototypical homeobox genes HOXA, is critical in T-ALL oncogenesis. IntroductionT-cell acute lymphoblastic leukemias (T-ALLs) are highly malignant tumors representing 10% to 15% of pediatric and 25% of adult ALLs in humans. 1,2 T-ALL cells derive from partially differentiated thymocytes. These cells originate from pluripotent progenitors that are progressively committed to the ␣␤ or ␥␦ T-cell lineages in the thymus. 3 Somatic V(D)J recombination rearranges the T-cell-receptor (TCR) gene segments, generating protein products that allow cells to pass through several cellular processes, so-called ␤-selection and selection. 4,5 Hence, V(D)J recombination both directly compromises genome integrity and indirectly controls cellular functions considered to be critical for oncogenesis, such as cell cycle, proliferation, and apoptosis. 6 However, T-ALLs remain rare, consistent with efficient control mechanisms that can only be overcome by accumulation of oncogenic events. Several classes of proto-oncogenes can be activated by chromosomal rearrangements or epigenetic mechanisms in T-ALL. [7][8][9] The resulting oncoproteins include basic helix-loop-helix proteins (TAL1/SCL, TAL2, LYL1), homeodomain-containing proteins (TLX1/HOX11, TLX3/HOX11L2), and LIM only proteins (LMO1, LMO2), which are likely to be involved in transcription factor complexes. 8,10 In addition, chromosomal alterations or DNA mutations can activate genes involved in signal transduction and thymus differentiation, such as NOTCH1 and LCK, [11][12][13] or can lead to gene fusion (MLL-ENL, CALM-AF10, NUP214-ABL1). [14][15][...

Leukaemic transformation by CALM–AF10 involves upregulation of Hoxa5 by hDOT1L

“…cDNA microarray studies have revealed that overexpression of late Hoxa genes and Bmi-1 are a characteristic of leukaemias involving CALM-AF10 and some MLL-fusion proteins [12][13][14] . In particular, over-expression of Hoxa9 has been demonstrated to be crucial for leukaemias involving MLL-ENL and MLL-AF10 fusion proteins 5,15,16 .…”

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.…”