Stem Cell Leukemia: how a TALented actor can go awry on the hematopoietic stage

Nc, Correia; Arcangeli, Marie-Laure; Pflumio, Françoise; Barata, João T.

doi:10.1038/leu.2016.169

Cited by 16 publications

(11 citation statements)

References 104 publications

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“…ITGB5 has been shown to contribute to tumor development in breast cancer, epithelial-mesenchymal transition and tumor potential in carcinoma cells [37, 38] and TAL1 is T-cell pro-oncogene with over-expression associated with development of leukemia. [39] ALOX12, CLU and ADRA2A were also upregulated in the A-T subjects but did not reach statistical difference compared to non A-T controls.…”

Section: Resultsmentioning

confidence: 80%

Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia

McGrath‐Morrow¹,

Ndeh²,

Collaco³

et al. 2018

PLoS ONE

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IntroductionClassic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid malignancies and telangiectasias. Prior studies have suggested that chronic inflammation and premature aging may contribute to the development of malignancy and pulmonary disease in people with A-T. To further examine the link between A-T and inflammation, we hypothesized that subjects with classic A-T would have greater enrichment of inflammatory pathways in peripheral blood mononuclear cells (PBMCs) compared to non A-T age-matched controls. To test this hypothesis we used RNAseq as an unsupervised approach to identify biological processes altered in people with classic A-T.MethodsPBMCs were isolated from subjects with classic A-T and compared to non-A-T age-matched healthy controls. RNAseq with differential gene expression analyses was then performed. Selected genes were validated by RT-qPCR using cohorts of subjects consisting of classic A-T, mild A-T or non-A-T controls. Subjects with mild A-T were characterized by later onset/mild neurologic features and normal/near normal immune status.ResultsRNAseq revealed 310 differentially expressed genes (DEGs) including genes involved in inflammation, immune regulation, and cancer. Using gene set enrichment analysis, A-T subjects were found to have biological processes enriched for inflammatory and malignancy pathways. In examining a cohort of A-T subjects in which baseline serum IL8 and IL6 levels were measured previously, an association was found between higher serum IL8 levels and higher likelihood of developing malignancy and/or death in a subsequent 4–6 year period.ConclusionRNAseq using PBMCs from subjects with classic A-T uncovered differential expression of immune response genes and biological processes associated with inflammation, immune regulation, and cancer. Follow-up of A-T subjects over a 4–6 year period revealed an association between higher baseline serum IL8 levels and malignancy/death. These findings support a role for inflammation as a contributing factor in A-T phenotypes.

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Section: Resultsmentioning

confidence: 80%

Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia

McGrath‐Morrow¹,

Ndeh²,

Collaco³

et al. 2018

PLoS ONE

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“…104 However, SCL expression can be activated in T cells through chromosomal translocations (interstitial deletions in the SIL-SCL locus) and mono/ biallelic transcriptional mechanisms. 105 This ectopic thymic expression is seen in 60% of childhood and adult T-ALL cases, often associated with poor prognosis. 55,106 Expression of SCL is, however, insufficient to induce overt leukemia.…”

Section: Scl In Leukemogenesismentioning

confidence: 99%

SCL/TAL1: a multifaceted regulator from blood development to disease

Porcher

Chagraoui

Kristiansen

2017

Blood

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SCL/TAL1 (stem cell leukemia/T-cell acute lymphoblastic leukemia [T-ALL] 1) is an essential transcription factor in normal and malignant hematopoiesis. It is required for specification of the blood program during development, adult hematopoietic stem cell survival and quiescence, and terminal maturation of select blood lineages. Following ectopic expression, SCL contributes to oncogenesis in T-ALL. Remarkably, SCL's activities are all mediated through nucleation of a core quaternary protein complex (SCL:E-protein:LMO1/2 [LIM domain only 1 or 2]:LDB1 [LIM domain-binding protein 1]) and dynamic recruitment of conserved combinatorial associations of additional regulators in a lineage- and stage-specific context. The finely tuned control of SCL's regulatory functions (lineage priming, activation, and repression of gene expression programs) provides insight into fundamental developmental and transcriptional mechanisms, and highlights mechanistic parallels between normal and oncogenic processes. Importantly, recent discoveries are paving the way to the development of innovative therapeutic opportunities in SCL T-ALL.

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“…The expression level of SIL in T-cells is normally very high, and, therefore, this translocation results in a high expression of the SIL-TAL1 fusion gene [ 55 ]. This deletion has been detected in 20–25% of patients with T-ALL [ 54 , 56 , 57 ]. However, in most TAL1-positive cases of T-cell leukemia, an abnormally high expression of TAL1 is effected without the participation of chromosomal rearrangements.…”

Section: The Functions Of the Scl Complex And Its Individual Componenmentioning

confidence: 99%

The Role of TAL1 in Hematopoiesis and Leukemogenesis

et al. 2018

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TAL1 (SCL/TAL1, T-cell acute leukemia protein 1) is a transcription factor that is involved in the process of hematopoiesis and leukemogenesis. It participates in blood cell formation, forms mesoderm in early embryogenesis, and regulates hematopoiesis in adult organisms. TAL1 is essential in maintaining the multipotency of hematopoietic stem cells (HSC) and keeping them in quiescence (stage G0). TAL1 forms complexes with various transcription factors, regulating hematopoiesis (E2A/HEB, GATA1-3, LMO1-2, Ldb1, ETO2, RUNX1, ERG, FLI1). In these complexes, TAL1 regulates normal myeloid differentiation, controls the proliferation of erythroid progenitors, and determines the choice of the direction of HSC differentiation. The transcription factors TAL1, E2A, GATA1 (or GATA2), LMO2, and Ldb1 are the major components of the SCL complex. In addition to normal hematopoiesis, this complex may also be involved in the process of blood cell malignant transformation. Upregulation of C-KIT expression is one of the main roles played by the SCL complex. Today, TAL1 and its partners are considered promising therapeutic targets in the treatment of T-cell acute lymphoblastic leukemia.

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Stem Cell Leukemia: how a TALented actor can go awry on the hematopoietic stage

Cited by 16 publications

References 104 publications

Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia

Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia

SCL/TAL1: a multifaceted regulator from blood development to disease

The Role of TAL1 in Hematopoiesis and Leukemogenesis

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