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

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLLrearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression-based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest. IntroductionT-cell acute lymphoblastic leukemia (T-ALL) is a thymocyte malignancy, and represents about 15% of pediatric patients with ALL. T-ALL often presents with a high tumor mass, accompanied by a rapid progression of disease. Still, about 30% of patients with T-ALL relapse during therapy or within the first 2 years following treatment and eventually die. 1 Over the last few years, great progress has been made in unravelling the genetics of T-ALL, including recurrent chromosomal translocations (TAL1, LYL1, LMO1, LMO2, HOX11/TLX1, HOX11L2/TLX3, MYB, and Cyclin D2), deletions (SIL-TAL1, del(6q), del(9)(p21), and del(11)(p12p13)), amplifications (NUP214-ABL1), duplications (MYB), and mutations (RAS and NOTCH1). [2][3][4][5][6][7][8][9][10][11][12][13] Some of these abnormalities are mutually exclusive and may delineate distinct T-ALL subgroups (ie, TAL1, LMO1, LMO2, HOX11, HOX11L2, MLL, and Inv(7)). Others are shared by some of these subgroups and may lead to the deregulation of cell cycle (ie, del(9)(p21) that includes the CDKN2A/p15 and CDKN2B/p16 loci). 3,4 Some may be acquired during leukemic growth, like the episomal NUP214-ABL1 amplification. 6 NOTCH1 activation mutations are present in more than half of all patients with T-ALL regardless of the presence of other rearrangements. 7 It has been hypothesized that activation of NOTCH1 represents one of the most advanced abnormalities in T-ALL that may enable for uncontrolled proliferation and/or inhibition of apoptosis, possibly through up-regulation of the target genes cMYC and DELTEX1. [14][15][16] In contrast to the wide variety of genetic abnormalities in T-ALL, initial microarray studies have revealed only 5 different expression clusters: immature/LYL1, TAL...

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

“…74 We and others have used SNP, BAC or oligo-array CGH platforms to identify deletions resulting to dysregulated expression of TAL1 38 and LMO2, 75 deletion of RB1, 38 deletion and mutation of PTEN, 38,76,77 deletion or mutation of the U3 ubiquitin ligase FBXW7, 76,78 amplification of MYB 38,79,80 and fusion of SET to NUP214. 81 T-ALL thus exhibits the similar genetic complexity to that observed in B-ALL. Studies integrating analysis of CNA, sequence mutations (for example, NOTCH1 18 and PTEN 77 ) will be important to accurately classify T-ALL and examine associations with treatment outcome.…”

An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

“…Juxtaposition with TCRB regulatory elements via translocation (7;7)(p15;q34) or inversion(7)(p15q34) directly activates HOXA by a cis-like mechanism; 12,13 however, the majority of HOXA locus deregulation has been described to occur in trans. Fusion proteins that arise from rearrangements involving the Mixed Lineage Leukemia gene (MLL) 4 , MLLT10 (formerly AF10) [14][15][16][17] and the SET-NUP214 translocation 18 have been shown to recruit DOT1 Ligand (DOT1L), which stimulates HOXA expression through aberrant methylation of Lys79 of Histone H3. 19,20 DOT1L is additionally known to methylate a range of target genes that are also likely to contribute to the leukemic phenotype, 21 and it is therefore probable that the molecular mechanisms of leukemogenesis within the HOXA Pos subgroup are heterogeneous.…”

The set gene is a potential oncogene in human colorectal adenocarcinoma and oral squamous cell carcinoma

“…These symptoms were in line with those of acute undifferentiated leukemia. Furthermore, van Vlierberghe et al (13) reported set-can gene fusion in T-cell acute lymphoblastic leukemia. These authors found that the fusion protein appeared to promote an elevated expression of the HOXA cluster genes (homeobox A, HOXA), which are key genes involved in hematopoietic stem cell proliferation and differentiation, that may cause leukemia, such as T-cell acute lymphoblastic leukemia.…”

“…It is predicted to encode a 277 amino acid protein with a molecular weight of 39 kDa. The set gene has been found to play a role in leukemia and ovarian cancer, but its role in the development of colorectal adenocarcinoma and oral squamous cell carcinoma remains to be elucidated (10)(11)(12)(13)(14)(15).…”