The mummified Hodgkin cell: cell death in Hodgkin's disease

Lorenzen, Johann; Thiele, Jüergen; Fischer, R.

doi:10.1002/(sici)1096-9896(199707)182:3<288::aid-path859>3.0.co;2-3

Cited by 26 publications

(7 citation statements)

References 32 publications

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“…Although further studies are needed, these findings suggest that inactivation of p53 by point mutation can occur in HD. However, it has also recently been suggested by Lorenzen et al (1997) (58) and Sanchez-Beato et al (1996) (59) that mutational inactivation of p53 is probably rare in HD. The p53 gene can downregulate cell cycling by induction of cyclin-dependent kinase inhibitors, in particular p21 (60).…”

Section: Attactactactact Acggtatggacgtct G G G G C C a A G G G~ Fggtcmentioning

confidence: 89%

Apoptosis‐related genes and proteins in Hodgkin's disease

Lauritzen

Möller

Nedergaard

et al. 1999

APMIS

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related genes and proteins in Hodgkin's disease. APMIS 1999; 107:63644.During recent years it has become increasingly evident that L&H cells in nodular lymphocytic predominance (LP) Hodgkin's disease (HD) and Hodgkin and Reed-Sternberg (H-RS) cells in approximately half the cases of classical HD originate from B-lymphocytes, and that H-RS cells in most of the remaining cases of classical HD express a null phenotype. The pathogenesis of HD is unknown. An association with Epstein-Barr virus (EBV) has been suggested and there are also indications that genes involved in programmed cell death (apoptosis) may be implicated. In this study, the expression of four apoptosis-related proteins (bcl-2, bcl-x, bax and p53) in 53 cases of HD was examined and the data were correlated with the genotype, the EBV status and the phenotype (B, T or null) of the neoplastic cells. The H-RS cells expressed a B-cell phenotype in 3/3 cases of nodular LP and in 19/ 50 (38%) cases of classical HD. The remaining cases showed a null-cell phenotype in 29/50 (58%) and a T-cell phenotype in 2/50 (4%). EBV was more often positive in B (14/19, 74%) than in null (7/29, 24%) type HD. The H-RS cells were bcl-2-positive in 19/53 (36%), bcl-x-positive in 17/53 (32%), baxpositive in 1/53, and p53-positive in 41/53 (77%) cases. No relationship was found between bcl-2 expression and EBV status, or between bcl-2 and bcl-x expression. A t( l4;18) translocation was seen in 2 of 34 cases. P53 point mutations were not detected. Our findings indicate that nodular LP and classical H D originate from B-cells in a high proportion of cases. They also suggest a role for bcl-2, bcl-x and p53 in tumorigenesis. The pathogenesis is not known at this stage.

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Section: Attactactactact Acggtatggacgtct G G G G C C a A G G G~ Fggtcmentioning

confidence: 89%

Apoptosis‐related genes and proteins in Hodgkin's disease

Lauritzen

Möller

Nedergaard

et al. 1999

APMIS

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“…The slow growth phenotype of Hodgkin and ReedSternberg cells is accompanied by frequent mitotic defects as well as a high incidence of apoptosis. 20 This suggests that Hodgkin and Reed-Sternberg cells might be actively proliferating cells that fail to accumulate due to an intrinsic failure to divide properly. Several proteins that regulate the mitotic cycle, such as cyclin D1, D3, E, B1, cyclin-dependent kinases 1, 2 and 6, S-phase kinase associated protein-2, p16 INK4A , p18 INK4c , p21 CIP1 , p27 KIP1 , p53, the retinoblastoma protein and PCNA have been found to be deregulated in classical Hodgkin's lymphoma.…”

Section: Discussionmentioning

confidence: 99%

“…Several proteins that regulate the mitotic cycle, such as cyclin D1, D3, E, B1, cyclin-dependent kinases 1, 2 and 6, S-phase kinase associated protein-2, p16 INK4A , p18 INK4c , p21 CIP1 , p27 KIP1 , p53, the retinoblastoma protein and PCNA have been found to be deregulated in classical Hodgkin's lymphoma. [1][2][3][4]6,[20][21][22][23][24][25][26] In the present study, we used a previously validated classical Hodgkin's lymphoma tissue microarray with a cohort of clinically well-documented cases 6,17,27 to analyze the expression of the cyclin-dependent kinase inhibitors of the Cip/Kipfamily, p21 CIP1 and p27 KIP1 , as well as two proliferation markers, PCNA and cyclin A. Since Hodgkin and Reed-Sternberg cells are embedded within reactive normal lymphocytes, we used those lymphocytes as internal controls for our staining Aberrant cell cycle regulation in Hodgkin's lymphoma A Tzankov et al conditions.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

et al. 2005

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The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G 1 -phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21 CIP1 and p27 KIP1 . Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S-or G 2 -phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21 CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27 KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G 1 -phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.

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“…[16][17][18][19][20][21][22][23][24] Cell culture conditions and the provenance, references, cellular origin and characterization of the remaining cell lines used in this study are given in Ref. 25.…”

Section: Cells and Culturementioning

confidence: 99%

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

MacLeod

Spitzer

Bar‐Am³

et al. 2000

Leukemia

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Although the neoplastic significance of the chromosome changes widespread in Hodgkin's disease (HD) remains obscure, a distinct cytogenetic picture has emerged combining aneuploidy with structural rearrangements clustered at certain breakpoints. Notably absent are the recurrent chromosome translocations which distinguish other hematopoietic neoplasms and serve as clues to underlying oncogene alterations. The paucity of neoplastic cells in HD biopsies hinders detailed chromosome analysis. As an alternative, we investigated a panel of well characterized cell lines by classical and molecular cytogenetics, using single-gene and subtelomeric probes, including three autologous HD examples (HDLM-1/2/3) analyzed by 'spectral karyotyping' -the first complete HD karyotype to be documented. Although complex, most rearrangements in HDLM cells arose in vivo and included few rare but many typical HD breakpoints, notably at the r(ibosomal)DNA regions. Two types of genomic rearrangement involving DNA repeats were conspicuous: insertion and genomic amplification/coamplification of rDNA -the first genomic rDNA rearrangements to be reported in a tumor cell, and the first example of multiple 'jumping translocations' (JT). Of four subtelomeric microsatellite repeats tested in HDLM cells, three exhibited interstitial sites at JT, of which two (at 5qter and 9pter) were respectively associated with deletion of the 5q31-32 myeloid region, and coamplification of a recently described HD-recurrent amplicon at 9p2 together with transcriptionally silent rDNA. Altogether, three out of four HD cell lines carried interstitial 9p subtelomeres and rDNA rearrangements. Taken together, these data suggest tumorigenic rearrangements may be facilitated by 'hitchhiking' along with mobile DNA repeat sequences which may target gene rearrangement at 9p in HD. Southern analysis of parallel rearrangements within rDNA intergenic spacers in HDLM cells highlighted several at, or near, retroposons. As well as validating HD cell lines as cytogenetic models, and resources for identifying genes rearranged in HD, our findings warrant further investigation of the roles of DNA repeat sequences, notably subtelomeric microsatellites, rDNA spacer sequences and retroposons as facilitators and markers of tumor-gene rearrangement.

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The mummified Hodgkin cell: cell death in Hodgkin's disease

Cited by 26 publications

References 32 publications

Apoptosis‐related genes and proteins in Hodgkin's disease

Apoptosis‐related genes and proteins in Hodgkin's disease

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

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