Expression of human recombination activating genes (RAG‐1 and RAG‐2) in angioimmunoblastic lymphadenopathy and anaplastic large cell lymphoma of T‐type

Knecht, Hans; Joske, David; Bachmann, Elias; Bachmann, Fédor; Odermatt, Bernhard; Pallesen, Gorm

doi:10.1111/j.1365-2141.1993.tb04706.x

Cited by 4 publications

(2 citation statements)

References 17 publications

(12 reference statements)

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“…In Hodgkin’s lymphoma the actual malignant cells make up only a very small proportion of the cell mass and studies on the accurate assessment of the cells of origin and key genetic events and mutations has lagged behind that of non-Hodgkin’s lymphoma. The cells of origin of classical Hodgkin’s disease is confirmed as germinal centre B cells which have completed VDJ rearrangement, with no ongoing recombinase activity [ 178 ] and have also undergone somatic hypermutation [ 179 , 180 ]. However it is apparent that these cells are unable to make functional immunoglobulin [ 179 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential

Savage

2015

BMC Cancer

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BackgroundA select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years. However for the more common metastatic malignancies chemotherapy treatment frequently brings clinical benefits but cure is not expected. Clinically this clear divide in outcome between the tumour types can appear at odds with the classical theories of chemotherapy sensitivity and resistance that include rates of proliferation, genetic development of drug resistance and drug efflux pumps. We have looked at the clinical characteristics of the chemotherapy curable malignancies to see if they have any common factors that could explain this extreme differential sensitivity to chemotherapy.DiscussionIt has previously been noted how the onset of malignancy can leave malignant cells fixed with some key cellular functions remaining frozen at the point in development at which malignant transformation occurred. In the chemotherapy curable malignancies the onset of malignancy is in each case closely linked to one of the unique genetic events of; nuclear fusion for molar pregnancies, choriocarcinoma and placental site trophoblast tumours, gastrulation for the childhood cancers, meiosis for testicular cancer and ovarian germ cell tumours and VDJ rearrangement and somatic hypermutation for acute leukemia and lymphoma. These processes are all linked to natural periods of supra-physiological apoptotic potential and it appears that the malignant cells arising from them usually retain this heightened sensitivity to DNA damage. To investigate this hypothesis we have examined the natural history of the healthy cells during these processes and the chemotherapy sensitivity of malignancies arising before, during and after the events.SummaryTo add to the debate on chemotherapy resistance and sensitivity, we would argue that malignancies can be functionally divided into 2 groups. Firstly those that arise in cells with naturally heightened apoptotic potential as a result of their proximity to the unique genetic events, where the malignancies are generally chemotherapy curable and then the more common malignancies that arise in cells of standard apoptotic potential that are not curable with classical cytotoxic drugs.

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Section: Discussionmentioning

confidence: 99%

Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential

Savage

2015

BMC Cancer

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“…ALCL seems to arise from mature T‐cells because V(D)J recombination has already been accomplished (60), and also other early markers such as CD34, TdT, and CD1a are no longer expressed. This finding might indicate that ALCL cells have dedifferentiated by a transformationlike event, similar to NPM/ALK‐mediated transformation of established 3T3 cells.…”

Section: Discussionmentioning

confidence: 99%

The cytoplasmic truncated receptor tyrosine kinase ALK‐ homodimer immortalizes and cooperates with ras in cellular transformation

et al. 2001

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Anaplastic large-cell lymphomas are highly associated with a chromosomal translocation t(2;5). This condition results in a chimeric protein NPM/ALK (nucleophosmin/anaplastic lymphoma kinase), in which the shuttle protein NPM is fused to the catalytic domain of the tyrosine receptor kinase ALK. Because the oncogenic potential of NPM/ALK is not well understood, we analyzed the effects of NPM/ALK and the specific contribution of ALK in a standardized cell culture system by using primary rat embryo cells (REC) as cellular targets. We demonstrate by several biological parameters that NPM/ALK is an immortalizing oncogene that provides unlimited, yet normal, growth potential to REC and, with cooperation with a c-H-ras oncogene, induces cellular transformation. Targeting NPM/ALK to the nucleus diminishes its oncogenicity, which indicates that the fusion protein exerts its action mainly in the cytoplasm. Expression of the mere catalytic domain of ALK is insufficient with regard to immortalization and transformation. However, reestablishing the potential of ALK to homodimerize by fusing the bacterial dimerization domain of the tetracycline repressor to ALK reenforces the immortalizing function. Collaboration of dimeric ALK with c-H-ras converted primary REC into aggressively growing tumor cell lines. These studies identify ALK as a new member of immortalizing oncoproteins that exerts its function within the cytoplasm.Key words: NPM/ALK • NPM/ALK constructs • primary rat embryo cells • immortalization • transformation • tumor formation naplastic large-cell lymphoma (ALCL) represents a distinct subgroup of non-Hodgkin's lymphomas (NHL) acknowledged in the Revised European and American Lymphoma classification. This entity constitutes ~5% of all NHL and accounts for ~30% of pediatric large-cell lymphomas (1). It is estimated that every year about 1000 new ALCL cases occur in the United States and 1200 new cases occur in Europe.(2). The majority of ALCL cases arising A in childhood (3, 4) have a characteristic chromosomal translocation t(2;5)(p23;q35). Morris et al. have cloned the genes affected by the chromosomal aberration (5). The rearrangement results in the fusion of a novel tyrosine kinase gene anaplastic lymphoma kinase (ALK) on chromosome 2p23 to the NPM (nucleophosmin/B23) gene on chromosome 5q35. The physiologic NPM encodes a highly conserved nonribosomal RNA-binding nucleolar phospho-protein, which is thought to function as a shuttle protein that transports ribosomal ribonucleoproteins between the nucleolus and the cytoplasm for assembly of ribosomes (6, 7). Both transcription and translation of ubiquitous NPM are cell cycle-regulated, which reach peak levels when cells prepare to enter S-phase, with a decrease to baseline values just before the onset of G2. In addition to its function as a shuttle protein, NPM was shown to bind to double-stranded DNA and to serve in the initiation and early elongation steps of DNA replication (8). The other fusion partner, ALK, shows sequence similarities to members of the insulin ...

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Lymphoid Neoplasms

2007

Jubb, Kennedy &Amp; Palmer's Pathology of Domestic Animals

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Expression of human recombination activating genes (RAG‐1 and RAG‐2) in angioimmunoblastic lymphadenopathy and anaplastic large cell lymphoma of T‐type

Cited by 4 publications

References 17 publications

Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential

Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential

The cytoplasmic truncated receptor tyrosine kinase ALK‐ homodimer immortalizes and cooperates with ras in cellular transformation

Lymphoid Neoplasms

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