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NPM‐ALK permits the survival of thymic T cells with aberrant T cell receptor rearrangements enabling thymic escape and tumor development

ABSTRACT: We present evidence to support a new model of Anaplastic Large Cell Lymphoma (ALCL) pathogenesis in which the malignancy is initiated in early thymocytes, prior to TCR rearrangement which is bypassed in NPM‐ALK transgenic mice following Notch1 expression. In support, we show that T cell receptor (TCR) rearrangements are aberrant in some human ALCL, yielding events that would not normally be permissive for survival during T cell development. However, a TCR is required for thymic egress and subsequent development of peripheral tumors in mice yet this TCR must be down‐regulated for T‐cell lymphomagenesis. Children affected by ALCL may thus harbor lymphoma-initiating cells in the thymocyte population that seeds relapse after chemotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67131 | GEO | 2016/01/05

SECONDARY ACCESSION(S): PRJNA279168

REPOSITORIES: GEO

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NPMâ??ALK permits the survival of thymic T cells with aberrant T cell receptor rearrangements enabling thymic escape and tumor development

Project description:We present evidence to support a new model of Anaplastic Large Cell Lymphoma (ALCL) pathogenesis in which the malignancy is initiated in early thymocytes, prior to TCR rearrangement which is bypassed in NPMâ??ALK transgenic mice following Notch1 expression. In support, we show that T cell receptor (TCR) rearrangements are aberrant in some human ALCL, yielding events that would not normally be permissive for survival during T cell development. However, a TCR is required for thymic egress and subsequent development of peripheral tumors in mice yet this TCR must be downâ??regulated for Tâ??cell lymphomagenesis. Children affected by ALCL may thus harbor lymphoma-initiating cells in the thymocyte population that seeds relapse after chemotherapy. comparative genomic hybridization data from 43 human Anaplastic Large Cell Lymphoma (ALCL) samples and control samples

2016-01-05 | E-GEOD-67131 | biostudies-arrayexpress

NPM-ALK expression levels identify two distinct signatures in Anaplastic Large Cell Lymphoma of Childhood

Project description:Anaplastic large-cell lymphoma (ALCL) makes up approximately 15% of paediatric non-Hodgkin's lymphomas of childhood. The vast majority of them is associated with the t(2;5)(p23;q35) translocation that results in the expression of a hybrid oncogenic tyrosine kinase, NPM-ALK. In order to investigate ALCL biological characteristics we used transcriptional profiling approach. Genome-wide gene expression profiling, performed on 23 paediatric ALCL and 12 reactive lymph nodes specimens, showed two novel ALCL subgroups based on their NPM-ALK expression levels (named (ALK low and ALK high). Gene set enrichment analysis revealed, in ALK low samples, a positive enrichment of genes involved in the Interleukin signaling pathway, whereas we found increased expression of genes related to cell cycle progression and division in ALK high tumour samples, such as Aurora Kinase A (AURKA) and B (AURKB). Growth inhibition was observed upon administration of AURKA and AURKB inhibitors Alisertib and Barasertib and it was associated with perturbation of the cell cycle and induction of apoptosis. In conclusion we identified two novel ALCL subgroups, which display unique biological characteristics suggesting sensitivity to distinct targeted therapies.

2016-11-04 | GSE78513 | GEO

Expression data from NPM-ALK T cell lymphoma in WT or WASP-deficient background

Project description:Total RNA was extracted from primary T cell lymphoma that spontaneously developed in either NPM-ALK or NPM-ALK/WASP-deficent transgenic mice

2018-11-08 | GSE102889 | GEO

ALK–transformed mature T lymphocytes restores early thymus progenitor features

Project description:Anaplastic large cell lymphoma (ALCL) is a mature T cell neoplasm that often expresses the CD4+ T cell surface marker. (It usually harbors the t(2;5) (p23;q35) translocation, leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. We demonstrated that in vitro transduction of normal human CD4+ T lymphocytes with NPM-ALK results in their immortalization and malignant transformation. The tumor cells displayed morphological and immunophenotypical characteristics of primary patient–derived anaplastic large cell lymphomas. Cell growth, proliferation, and survival were strictly dependent on NPM-ALK activity and include activation of the key factors STAT3 and DNMT1 and expression of CD30 (the hallmark of anaplastic large-cell lymphoma). Implantation of NPM-ALK–transformed CD4+ T lymphocytes into immunodeficient mice resulted in the formation of tumors indistinguishable from patients’ anaplastic large cell lymphomas. Integration of “Omic” data revealed that NPM-ALK–transformed CD4+ T lymphocytes and primary NPM-ALK+ ALCL biopsies share similarities with early T cell precursors. Of note, these NPM-ALK+ lymphoma cells overexpress stem cell regulators (OCT4, SOX2, and NANOG) and HIF2A, which is known to affect hematopoietic precursor differentiation and NPM-ALK+ cell growth. Altogether, for the first time our findings suggest that NPM-ALK could restore progenitor-like features in mature CD30+ peripheral CD4+ T cells, in keeping with a thymic progenitor-like pattern.

2020-12-07 | GSE160123 | GEO

NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes

Project description:Nucleophosmin (NPM1) is either frequently mutated or subjected to chromosomal translocation in acute myeloid leukemia (AML). NPM protein is primarily located in the nucleus, but the recurrent NPMc+ mutation is characterized by cytoplasmic localization and leukemogenic properties. Similarly, the NPM-MLF1 translocation product favors the partial cytoplasmic retention of NPM. Regardless of their common cellular distribution, NPM-MLF1 malignancies engender different effects on hematopoiesis compared to NPMc+ counterparts, highlighting possible aberrant nuclear function(s) of NPM in NPMc+ AML. We performed a proteomics analysis and found that NPM and NPM-MLF1 interact with chromatin remodeling complexes of the ISWI family, as well as with NuRD and P/BAF complexes. Accordingly, NPM and NPM-MLF1 are recruited to transcriptionally active or repressed genes along with NuRD and P/BAF elements. Although the overall gene expression program in NPM knockdown cells is similar to that resulting from NPMc+ and is consistent with loss of nuclear function of NPM, NPM-MLF1 expression differentially altered gene transcription regulated by NPM. The abnormal gene regulation imposed by NPM-MLF1 is characterized by enhanced recruitment of NuRD to gene regulatory regions. Thus, different mechanisms orchestrate the deregulation of NPM function in NPMc+- versus NPM1-MLF1-associated leukemia.

2019-10-17 | GSE124495 | GEO

NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes

Project description:Nucleophosmin (NPM1) is either frequently mutated or subjected to chromosomal translocation in acute myeloid leukemia (AML). NPM protein is primarily located in the nucleus, but the recurrent NPMc+ mutation is characterized by cytoplasmic localization and leukemogenic properties. Similarly, the NPM-MLF1 translocation product favors the partial cytoplasmic retention of NPM. Regardless of their common cellular distribution, NPM-MLF1 malignancies engender different effects on hematopoiesis compared to NPMc+ counterparts, highlighting possible aberrant nuclear function(s) of NPM in NPMc+ and NPM-MLF1 AML. We performed a proteomics analysis and found that NPM and NPM-MLF1 interact with chromatin remodeling complexes of the ISWI family, as well as with NuRD and P/BAF complexes. Accordingly, NPM and NPM-MLF1 are recruited to transcriptionally active or repressed genes along with NuRD and P/BAF elements. Although the overall gene expression program in NPM knockdown cells is similar to that resulting from NPMc+ and is consistent with loss of nuclear function of NPM, NPM-MLF1 expression differentially altered gene transcription regulated by NPM. The abnormal gene regulation imposed by NPM-MLF1 is characterized by enhanced recruitment of NuRD to gene regulatory regions. Thus, different mechanisms orchestrate the deregulation of NPM function in NPMc+ -versus NPM1-MLF1- associated leukemia.

2019-10-18 | PXD012305 | Pride

npm

Project description:Re-sequencing of npm mutants and siblings

| PRJEB32642 | ENA

NPM-ALK metabolic regulation

Project description:The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis. Research is published: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739039/

2013-09-24 | ST000016 | MetabolomicsWorkbench

Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK driven lymphomagenesis [RRBS]

Project description:Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T cell-specific lymphoma model based on the human oncogenic NPM-ALK translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis

2020-12-08 | GSE162217 | GEO

Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK driven lymphomagenesis [RNA-Seq]

2020-12-08 | GSE162216 | GEO

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