Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma

Eckerle, Susan; Brune, Verena; Döring, Claudia; Tiacci, Enrico; Bohle, Verena; Sundström, Christer; Kodet, Roman; Paulli, Marco; Falini, Brunangelo; Klapper, Wolfram; Chaubert, A. B.; Willenbrock, Klaus; Metzler, Dirk; Bräuninger, Andreas; Küppers, Ralf; Ml, Hansmann

doi:10.1038/leu.2009.161

Cited by 123 publications

(121 citation statements)

References 43 publications

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“…Described and validated targets for miR-101 include mTOR (31), the antiapoptotic protein Mcl1 (39), and the histone methyltransferase EZH2 (40,41). In support of our data, Mcl1 and EZH2 have been reported as overexpressed in ALK + ALCL as well as in ALK − ALCL (8,33,42). Also, activity of the mTOR pathway is enhanced in ALK + ALCL but not in ALK − ALCL (7,8).…”

Section: Discussionsupporting

confidence: 76%

“…ALCL (32). Furthermore, several groups have demonstrated that unsupervised clustering of gene expression profiles is not able to separate ALK + from ALK − ALCL (33)(34)(35). However, using supervised analysis, genes were identified that are differentially expressed, many of which are regulated by STAT3 (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several groups have demonstrated that unsupervised clustering of gene expression profiles is not able to separate ALK + from ALK − ALCL (33)(34)(35). However, using supervised analysis, genes were identified that are differentially expressed, many of which are regulated by STAT3 (33)(34)(35). In the study by Piva et al (35), a five-gene classifier (IL1RAP, GAS1, PRF1, IL2RA, and TMEM158) with a specificity and selectivity of more than 95% separates ALK + from ALK − ALCL.…”

Section: Discussionmentioning

confidence: 99%

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Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Merkel

Hamacher

Laimer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

107

133

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Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK + from ALK − subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK + and ALK − ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK + ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK − ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK + and not in ALK − cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.micro-RNA | mTOR | miR-155 | miR-101

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Merkel

Hamacher

Laimer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

107

133

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“…The expression of almost the whole GIMAP family is turned down in regulatory T cells of patients suffering from T1D (18). Furthermore, GIMAPs belong to the most down-regulated proteins in anaplastic large cell lymphomas compared to the progenitor T cells (19). In contrast, overexpression of GIMAPs was implicated in certain types of leukemia (20) and lung cancer (21).…”

mentioning

confidence: 99%

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Schwefel

Fröhlich²,

Eichhorst³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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GTPases of immunity-associated proteins (GIMAPs) are a distinctive family of GTPases, which control apoptosis in lymphocytes and play a central role in lymphocyte maturation and lymphocyte-associated diseases. To explore their function and mechanism, we determined crystal structures of a representative member, GIMAP2, in different nucleotide-loading and oligomerization states. Nucleotide-free and GDP-bound GIMAP2 were monomeric and revealed a guanine nucleotide-binding domain of the TRAFAC (translation factor associated) class with a unique amphipathic helix α7 packing against switch II. In the absence of α7 and the presence of GTP, GIMAP2 oligomerized via two distinct interfaces in the crystal. GTP-induced stabilization of switch I mediates dimerization across the nucleotide-binding site, which also involves the GIMAP specificity motif and the nucleotide base. Structural rearrangements in switch II appear to induce the release of α7 allowing oligomerization to proceed via a second interface. The unique architecture of the linear oligomer was confirmed by mutagenesis. Furthermore, we showed a function for the GIMAP2 oligomer at the surface of lipid droplets. Although earlier studies indicated that GIMAPs are related to the septins, the current structure also revealed a strikingly similar nucleotide coordination and dimerization mode as in the dynamin GTPase. Based on this, we reexamined the relationships of the septin-and dynamin-like GTPases and demonstrate that these are likely to have emerged from a common membrane-associated dimerizing ancestor. This ancestral property appears to be critical for the role of GIMAPs as nucleotide-regulated scaffolds on intracellular membranes. G protein | protein structure

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“…While published data on the potential role of NF-κB in the various subgroups of PTCL remain -for the most part -inconclusive, there is some evidence that NF-κB expression may be lower in ALCL than in PTCL-NOS. 36,37 Since in our hands none of the commercially available antibodies directed against the NF-κB subunits led to reliable staining results, we decided to investigate the expression of the upstream located molecules Carma1/Card11 and Bcl-10 which are part of the trimolecular CBM-complex that is assembled after TCR stimulation. 38 Given that there appeared to be no significant differences in expression in Bcl-10 and Carma1 when comparing the whole group of systemic and primary cutaneous CD30 + lymphoproliferations with PTCL-NOS, these proteins are unlikely to be responsible for the varying activity of NF-κB and expression of its target genes between PTCL subgroups.…”

mentioning

confidence: 99%

Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations

Geissinger¹,

Sadler²,

Roth³

et al. 2010

Haematologica

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ConclusionsSeverely altered expression of the T-cell receptor/CD3 complex, T-cell receptor-associated transcription factors and signal transduction molecules is a common characteristic of systemic and cutaneous CD30 + lymphoproliferations, although the clinical behavior of these entities is very different. Since peripheral T-cell lymphomas, not otherwise specified retain the full expression program required for functioning T-cell receptor signaling, the differential expression of a subset of these markers might be of diagnostic utility in distinguishing peripheral T-cell lymphomas, not otherwise specified from the entire group of CD30 + lymphoproliferations.Key words: systemic and cutaneous CD30 + lymphoproliferations, anaplastic large cell lymphoma, lymphomatoid papulosis, ALCL, LyP, TCR.Citation: Geissinger E, Sadler P, Roth S, Grieb T, Puppe B, Müller N, Reimer P, Vetter-Kauczok CS, Wenzel J, Bonzheim I, Rüdiger T, Müller-Hermelink HK, and Rosenwald A. Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations. Haematologica 20010;95(10):1697-1704. doi:10.3324/haematol.2009 This is an open-access paper. Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30 + T-cell lymphoproliferations © F e r r a t a S t o r t i F o u n d a t i o nIntroduction CD30 + T-cell lymphoproliferations comprise a spectrum of clinically heterogeneous entities, including systemic anaplastic large cell lymphomas (ALCL) as well as primary cutaneous CD30 + T-cell lymphoproliferative disorders. Morphologically, these entities are characterized by the proliferation of highly atypical, anaplastic CD30 + T cells. Despite the frequent detection of clonally rearranged Tcell receptor (TCR) genes, the expression of T-cell-specific antigens in the tumor cells is not consistently detectable. 1 Systemic ALCL comprise approximately 15% of all peripheral T-cell lymphomas (PTCL) in Europe 2 and are divided into anaplastic lymphoma kinase (ALK) positive and negative subgroups (ALK + and ALK -systemic ALCL), whereas primary cutaneous CD30 + T-cell lymphoproliferative disorders represent a spectrum of skin lesions with diverging and in part overlapping clinical and morphological features. CD30 + T-cell lymphoproliferative disorders include primary cutaneous ALCL, lymphomatoid papulosis and so-called borderline lesions, [3][4][5] but even with the knowledge of the clinical presentation and a detailed morphological and immunohistochemical picture it is sometimes difficult, if not impossible, to classify a particular cutaneous lesion correctly.While the transforming properties of ALK over-expression have been clearly demonstrated ,6,7 the transformation mechanisms in ALK -systemic ALCL and primary cutaneous CD30 + T-cell lymphoproliferative disorders are poorly understood. CD30 itself, a cytokine receptor belonging to the tumor necrosis factor receptor superfamily, has been a research focus over the past years, but whether CD30 signaling lea...

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Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma

Cited by 123 publications

References 43 publications

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations

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Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma

Cited by 123 publications

References 43 publications

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+and ALK−anaplastic large-cell lymphoma

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+and ALK−anaplastic large-cell lymphoma

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations

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Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma