Circulating t(2;5)-positive cells can be detected in cord blood of healthy newborns

Laurent, Césari; Lopez, Celine; Desjobert, Cécile; Berrébi, Alain; Damm‐Welk, Christine; Delsol, Georges; Brousset, Pierre; Lamant, Laurence

doi:10.1038/leu.2011.209

Cited by 21 publications

(14 citation statements)

References 8 publications

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“…Previously, we have shown that ALCL-propagating cells express a gene signature associated with an ETP in keeping with a presumed thymic origin as described in the current model 32 . Indeed, NPM–ALK transcripts have been detected in 2% of newborn cord blood 33 and expression of NPM–ALK is regulated by the endogenous NPM1 promoter, which drives ubiquitous expression of NPM1 including in thymic progenitors ( Supplementary Fig. 10 ).…”

Section: Discussionmentioning

confidence: 99%

Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress

et al. 2016

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Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) β-rearrangement, which is bypassed in CD4/NPM–ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRα but no comparable clonal TCRβ rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress

et al. 2016

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“…Identification of the tumour propagating or cancer stem cell for ALCL identified a gene signature characteristic of an early thymic progenitor within this distinct cellular subset (Moti et al , ). In support of this concept, NPM1‐ALK transcripts were detectable in 2/103 samples of newborn cord blood sampled from an otherwise healthy population (Laurent et al , ). Together these data suggest that the generation of the t(2;5) may be an early event occuring in primitive haemopoietic cells and perhaps requiring a thymic environment or at least T cell‐specific events for transformation although rare ALK+ B cell lymphomas do exist (Laurent et al , ).…”

Section: Phenotype and Cell Of Originmentioning

confidence: 92%

Anaplastic large cell lymphoma in paediatric and young adult patients

Lamant²,

et al. 2016

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Anaplastic large cell lymphoma (ALCL) is a heterogeneous disease of debateable origin that, in children, is largely anaplastic lymphoma kinase (ALK) positive with aberrant ALK activity induced following the formation of chromosomal translocations. Whilst the survival rates for this disease are relatively high, a significant proportion (20-40%) of patients suffer disease relapse, in some cases on multiple occasions and therefore suffer the toxic side-effects of combination chemotherapy. Traditionally, patients are treated with a combination of agents although recent data from relapse patients have suggested that low risk patients might benefit from single agent vinblastine and, going forward, the addition of ALK inhibitors to the therapeutic regimen may have beneficial consequences. There are also a plethora of other drugs that might be advantageous to patients with ALCL and many of these have been identified through laboratory research although the decision as to which drugs to implement in trials will not be trivial.

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“…Historically, mature T cells were presumed to be the targets for transformation, based on gene expression profiling and the presence of surface markers such as CD4 or CD30, as well as production of cytotoxic proteins such as Granzyme B and Perforin (Benharroch et al, 1998; Eckerle et al, 2009; Swerdlow et al, 2008). However, ALK+ cells are present in stem cell-enriched cord blood, and a study has identified a side population of cells in ALK+ ALCL cell lines and tumors with signatures similar to early thymic progenitors (ETPs), suggesting that transformation of T cells by NPM-ALK might occur early during thymic T cell development (Laurent et al, 2012; Moti et al, 2015). Subsequently, a mechanism has been proposed whereby in a murine mimic of ALK+ ALCL transient expression of a functional TCR is required for thymic emigration of incipient, thymic-resident tumor cells, but the TCR is then downregulated for peripheral lymphomagenesis (Malcolm et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling

et al. 2016

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SummaryAberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK−) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK− ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy.

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Circulating t(2;5)-positive cells can be detected in cord blood of healthy newborns

Abstract: RK et al. Patterned CpG methylation of silenced B cell gene promoters in classical Hodgkin lymphoma-derived and primary effusion lymphoma cell lines.

Cited by 21 publications

References 8 publications

Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress

Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress

Anaplastic large cell lymphoma in paediatric and young adult patients

Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling

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