Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia

Abstract

Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development: LYL1+ signature (pro-T), HOX11+ (early cortical thymocyte), and TAL1+ (late cortical thymocyte). Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T cell leukemogenesis. These findings have clinical importance, since HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or, surprisingly, HOX11L2 confers a much worse response to treatment. Our results illustrate the power of gene expression profiles to elucidate transformation pathways relevant to human leukemia.

Class struggle: expression profiling and categorizing cancer

“…15 The microarray results were confirmed with RT-PCR, and, as with the other studies, demonstrated that expression signatures could be used as prognostic indicators.…”

“…10 The ALL studies reported signatures in terms of their correlation with cytogenetic and gene fusion events. 14,15 Given the variety of descriptors appearing in the literature, the need has clearly arisen for a concise naming convention that is based upon inherent, robust properties of expression signatures.…”

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

“…19,20 In support of this hypothesis, several reports have shown a striking correlation between LMO2, TAL1, and Olig2 based on gene expression analysis in human and murine T-cell leukemia. [21][22][23] In future studies, it will be interesting to explore whether LMO2 interacts with Olig2 to regulate GSCs and brain tumorigenesis. Presence of tumor-derived vascular components sheds light on the plasticity of cancer cells and the potential involvement of cancer stem cells in cancer-associated angiogenesis.…”

p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice

“…Although Tal1 induces leukemia in mice, it does so after a long latency revealing that additional genetic events are required (Condorelli et al, 1996;Kelliher et al, 1996). Analysis of the INK4A/ARF locus in human T-ALL patients has revealed frequent homozygous deletion of exon 2, the exon common to both p16 INK4A and p14 ARF genes (Hebert et al, 1994;Cayuela et al, 1995Cayuela et al, , 1996Drexler, 1998;Gardie et al, 1998;Ferrando et al, 2002). Other T-ALL patients also exhibit alterations in the INK4A/ ARF locus that affect either p16 INK4A or p14 ARF only.…”

“…Specifically, in some cases, T-ALL patients exhibit methylation of the p16 INK4A promoter, whereas others display specific loss of p14 ARF , as detected by loss of exon 1b (Batova et al, 1997;Drexler, 1998;Gardie et al, 1998). Of TAL1-expressing T-ALL patients, 92% (13/14) have been shown to delete the shared exon 2, suggesting that loss of both p16 INK4A and p14 ARF may be required to cooperate with ectopic TAL1 activation (Ferrando et al, 2002). Moreover, clinical studies have suggested that INK4A/ARF deletions are a poor prognostic indicator, highlighting the need for additional therapies to treat these T-ALL patients (Kees et al, 1997;Zhou et al, 1997;Harrison, 2001).…”