Cryptic XPO1-MLLT10 translocation is associated with HOXA locus deregulation in T-ALL

Bond, Jonathan; Bergon, Aurélie; Durand, Alexandra; Tigaud, Isabelle; Thomas, Xavier; Asnafi, Vahid; Spicuglia, Salvatore; Macintyre, Elizabeth

doi:10.1182/blood-2014-04-567636

Cited by 20 publications

(19 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Missense substitutions targeting XPO1 have also previously been reported at a low frequency (<5%) in chronic lymphocytic leukemia (CLL) and esophageal squamous cell carcinoma (ESCC), suggesting that these XPO1 mutations may also play a role in several oncogenic processes. [29][30][31] Importantly, alternative XPO1 variants, including those located at the hotspot, 14,15,32,33 were not assessed by our dPCR approaches and we may have underestimated the rate of XPO1 mutations in cHL. Nevertheless, we did not detect those alternative XPO1 variants by NGS on cHL biopsies.…”

Section: Discussionmentioning

confidence: 99%

Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma

Camus¹,

Stamatoullas²,

Mareschal³

et al. 2016

Haematologica

102

112

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma

Camus¹,

Stamatoullas²,

Mareschal³

et al. 2016

Haematologica

102

112

View full text Add to dashboard Cite

“…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.…”

Section: An Early Thymic Precursor Phenotype Predicts Outcome Exclusimentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

G ene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXApositive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursorlike acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected eventfree survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia. Trial Registration: The GRAALL-2003 and studies were registered at

show abstract

“…XRCC1 polymorphisms are likely linked to the risk of lung cancer in Caucasian population 51. Cryptic XPO1 – MLLT10 translocation was related to homeobox A-locus deregulation in T-cell acute lymphoblastic leukemia 52. Here, the results of our meta-analysis under all genetic models showed that the rs12770228 polymorphism of MLLT10 was significantly associated with increased meningioma risk.…”

Section: Discussionmentioning

confidence: 58%

“…In addition to folate-metabolism genes, susceptibility loci of drug metabolism-related genes GSTM1 and GSTT1 , apoptosis-associated gene CASP8 , DNA repair-associated gene XRCC1 , and chromosomal rearrangement-associated gene MLLT10 have also been reported in various clinical diseases 48–52. For instance, GSTM1 and GSTT1 polymorphisms might be associated with renal cell carcinoma risk or treatment outcomes of breast cancer 48,49…”

Section: Discussionmentioning

confidence: 99%

Genetic variants and increased risk of meningioma: an updated meta-analysis

Han

Wang

et al. 2017

OTT

View full text Add to dashboard Cite

PurposeVarious genetic variants have been reported to be linked to an increased risk of meningioma. However, no confirmed conclusion has been obtained. The purpose of the study was to investigate potential meningioma-associated gene polymorphisms, based on published evidence.Materials and methodsAn updated meta-analysis was performed in September 2016. After electronic database searching and study screening, we selected eligible case-control studies and extracted data for meta-analysis, using Mantel–Haenszel statistics. P-values, pooled odds ratios (ORs), and 95% confidence intervals were calculated.ResultsWe finally selected eight genes with ten polymorphisms: MLLT10 rs12770228, CASP8 rs1045485, XRCC1 rs1799782, rs25487, MTHFR rs1801133, rs1801131, MTRR rs1801394, MTR rs1805087, GSTM1 null/present, and GSTT1 null/present. Results of meta-analyses showed that there was increased meningioma risk in case groups under all models of MLLT10 rs12770228 (all OR >1, P<0.001), compared with control groups. Similar results were observed under the allele, homozygote, dominant, and recessive models of MTRR rs1801394 (all OR >1, P<0.05), and the heterozygote and dominant models of MTHFR rs1801131 in the Caucasian population (all OR >1, P<0.05). However, no significantly increased meningioma risks were observed for CASP8 rs1045485, XRCC1 rs25487, rs1799782, MTHFR rs1801133, MTR rs1805087, or GSTM1/GSTT1 null mutations.ConclusionOur updated meta-analysis provided statistical evidence for the role of MLLT10 rs12770228, MTRR rs1801394, and MTHFR rs1801131 in increased susceptibility to meningioma.

show abstract

Cryptic XPO1-MLLT10 translocation is associated with HOXA locus deregulation in T-ALL

Cited by 20 publications

References 10 publications

Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma

Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma

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

Genetic variants and increased risk of meningioma: an updated meta-analysis

Contact Info

Product

Resources

About