Extensive molecular mapping of TCRα/δ- and TCRβ-involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL

Noir, Sandrine Le; Abdelali, Raouf Ben; Lelorc’h, Marc; Bergeron, Julie; Sungalee, Stéphanie; Payet-Bornet, Dominique; Villarèse, Patrick; Petit, Arnaud; Callens, Céline; Lhermitte, Ludovic; Baranger, Laurence; Radford‐Weiss, Isabelle; Grégoire, Marie-Josée; Dombret, Hervé; Ifrah, Norbert; Spicuglia, Salvatore; Romana, Serge; Soulier, Jean; Nadel, Bertrand; Macintyre, Elizabeth; Asnafi, Vahid

doi:10.1182/blood-2012-04-425488

Cited by 32 publications

(37 citation statements)

References 38 publications

(58 reference statements)

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“…60 T-ALLs have heterogeneous karyotypes, with about half being aneuploid and the remainder containing translocations including oncogenic Tcrα/δ translocations. [61][62][63] Although inactivating TP53 mutations are not common in T-ALL, these genetic lesions are often associated with drug resistance, rapid disease progression, and poor survival. 3 Therefore, LP mice may provide a useful preclinical model to evaluate the potential efficacy of more specific and less toxic treatments for T-ALL with TP53 inactivation.…”

Section: Discussionmentioning

confidence: 99%

Somatic inactivation of Tp53 in hematopoietic stem cells or thymocytes predisposes mice to thymic lymphomas with clonal translocations

2013

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Section: Discussionmentioning

confidence: 99%

Somatic inactivation of Tp53 in hematopoietic stem cells or thymocytes predisposes mice to thymic lymphomas with clonal translocations

2013

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“…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.…”

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

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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

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“…Microarray analysis showed hypomethylation is identified near 14 genes including NKX2.4 and NKX2.5 that encoding predominantly transcription factors [44] . In another study, NKX2.4 was detected as one of previously unreported TCRtranslocated oncogene partners in 280 T-cell acute lymphoblastic leukemia (T-ALL) when Le Noir et al screening for TCRβ and TCRα/δ translocations [45] . Up till the present moment, there is still no evidence to show the interrelation between NKX2.4 and gastrointestinal neoplasms.…”

Section: Nkx24mentioning

confidence: 99%

The homeobox NKX and Neoplasms in Digestive system: a systematic review.

Yao¹,

Zhu²

2017

RAJAR

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ABSTRACT:The incidence of digestive system neoplasms is increasing over these years due to the limitation of prompt diagnosis and effective treatment. Homeobox genes are usually associated with development of cancer. Previous studies indicate that homeobox NKX transcription factors are partly involved in the development and progression of tumors in gastrointestinal tract. To summarize the different impact of NKX genes have on the digestive system, the interrelationship between each NKX genes and gastric-derived tumors is analyzed as much detail as possible. The results turn out that some of NKX genes may be used as a target to distinguish the primary site of cancer, or as a biomarker to predict the therapeutic effect and survival which is instructive and meaningful to the future medical managements. This review is a systematic synopsis of research on the homeobox genes NKX and digestive system neoplasms, with the focus on their functions and clinical significance.

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Extensive molecular mapping of TCRα/δ- and TCRβ-involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL

Cited by 32 publications

References 38 publications

Somatic inactivation of Tp53 in hematopoietic stem cells or thymocytes predisposes mice to thymic lymphomas with clonal translocations

Somatic inactivation of Tp53 in hematopoietic stem cells or thymocytes predisposes mice to thymic lymphomas with clonal translocations

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

The homeobox NKX and Neoplasms in Digestive system: a systematic review.

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