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E Campo

Publications and source records attributed to E Campo.

At least 73 records · Page 4Linked to original sources
PubMed1999

c-myc mRNA expression and genomic alterations in mantle cell lymphomas and other nodal non-Hodgkin's lymphomas.

Cyclin D1 is a weak oncogene that cooperates with c-myc activation in the development of B cell lymphomas in transgenic animals. Cyclin D1 is constantly overexpressed in human mantle cell lymphomas (MCL). However, the status of c-myc gene in these tumors is not known. We have examined the c-myc mRNA expression and genomic alterations, including mutational analysis of exon 1, intron 1, and exon 2 regulatory elements, in a series of 33 MCL, 22 typical and 11 blastoid variants. In addition, c-myc alterations were also examined in 56 nodal non-Hodgkin's lymphomas (NHL). c-myc mRNA overexpression was found in 38% (11/29) of MCL with a slightly higher frequency in blastoid variants (5/10, 50%) than in typical cases (6/19, 31%). Genetic alterations were only found in one blastoid MCL showing a three-fold c-myc gene amplification. In other nodal NHL, c-myc overexpression was found in 24% (7/29) of indolent tumors but in 70% (19/27) of aggressive variants. c-myc Genetic alterations detected in these cases were gene rearrangement and hypermutations in one Burkitt's lymphoma, and individual point mutations in intron 1 or exon 2 in 1/19 (5%) indolent and 7/16 (44%) aggressive variants. These results indicate that c-myc is overexpressed in a subset of MCL, but structural gene alterations are less frequent than in other nodal NHL.

Blotting, Southern↗
PubMed1999

Possible carcinogenic effects of X-rays in a transgenerational study with CBA mice.

A lifetime experiment using 4279 CBA/J mice was carried out to investigate whether the pre-conceptual exposure of sperm cells to X-ray radiation or urethane would result in an increased cancer risk in the untreated progeny, and/or increased susceptibility to cancer following exposure to a promoting agent. The study consisted of four main groups, namely a control group (saline), a urethane group (1 mg/g body wt) and two X-ray radiation groups (1 Gy, 2 Gy). At 1, 3 and 9 weeks after treatment, the males of these four parental groups were mated with untreated virgin females. The offspring of each parental group was divided into two subgroups: one received s.c. urethane (0.1 mg/g body wt once) as a promoter, the other saline, at the age of 6 weeks. All animals were evaluated for the occurrence of tumours. K-ras oncogene and p53 tumour suppressor gene mutations were investigated in frozen lung tumour samples. The female offspring of male parents exposed to X-rays 1 week before their mating showed a trend towards a higher tumour incidence of the haematopoietic system than the F1 controls. In addition, a higher percentage of bronchioloalveolar adenocarcinomas in male offspring born to irradiated paternals mated 1 week after X-ray treatment points to a plausible increased sensitivity of post-meiotic germ cell stages towards transgenerational carcinogenic effects. On the other hand, no increased tumour incidence and malignancy were observed in the offspring born to irradiated paternals mated 3 and 9 weeks after X-ray treatment. Paternal urethane treatment 1, 3 and 9 weeks prior to conception did not result in significantly altered incidence or malignancy of tumours of the lung, liver and haematopoietic tissue in the offspring. K-ras mutations increased during tumour progression from bronchioloalveolar hyperplasia to adenoma. Codon 61 K-ras mutations were more frequent in lung tumours of urethane-promoted progeny from irradiated parents than from control parents. P53 mutations were absent from these lung alterations.

Adenocarcinoma↗
PubMed1999

Primary nodal marginal zone lymphomas of splenic and MALT type.

The existence of primary nodal marginal zone lymphomas (MZL) is controversial, as is their relationship to putative extranodal counterparts. Most nodal lymphomas with monocytoid B cell/marginal zone differentiation exhibit the morphologic and immunophenotypical characteristics of extranodal MALT-lymphomas. Splenic marginal zone lymphoma (SMZL) is also of putative marginal zone derivation, but it differs immunophenotypically from MALT lymphoma. To clarify the relationship between nodal and extranodal MZLs and to investigate the possible existence of a nodal variant of SMZL, 36 MZL initially considered to be primary nodal neoplasms were examined. Other low-grade lymphomas with marginal zone differentiation were excluded (small lymphocytic lymphoma/chronic lymphocytic leukemia [SLL/CLL], follicular lymphoma, and mantle cell lymphoma). Six nodal MZLs showed morphologic and phenotypic characteristics similar to those of SMZL, whereas 30 tumors were more similar to MALT-type lymphomas. The six tumors with SMZL features showed a polymorphic infiltrate surrounding residual germinal centers with absent or very attenuated mantle cuffs. These lymphomas were IgD positive (6/6) but cyclin D1 (0/5), CD5 (0/6), and CD23 (0/6) negative. Five of these patients came for treatment in stage I or II. No patient manifested splenomegaly, peripheral blood, and/or bone marrow infiltration either at diagnosis or during follow-up. Lymph nodes from 30 patients with MALT-type features showed a perisinusoidal and perivascular infiltration of monocytoid/centrocytoid cells and residual germinal centers with a relatively well-preserved mantle cuff. The neoplastic cells were negative for IgD (0/17), cyclin D1 (0/8), and CD5 (0/12). Seven of 16 (44%) patients with a detailed history and clinical follow-up had evidence of extranodal lymphoma. These observations suggest that most nodal B cell lymphomas with marginal zone differentiation are of the MALT type and that they are frequently associated with an extranodal component. In addition, a primary nodal counterpart of splenic MZL also exists, and may occur in the absence of splenomegaly.

Adult↗
PubMed1999

Beta-HCG aberrant expression in primary mediastinal large B-cell lymphoma.

We report on a primary mediastinal large B-cell lymphoma with aberrant expression of beta-human chorionic gonadotropin (beta-hCG). The patient, a 33-year-old man, had cough, dyspnea, fever, superior vena cava syndrome, and a mediastinal bulky tumor. A biopsy showed that the latter was characterized by large cells, sclerosis, and compartmentalization. The neoplastic elements expressed CD45, CD20, CD79a and, partially, CD30, whereas they were negative for CD3, epithelial membrane antigen and cytokeratins. Surprisingly, they displayed a clear-cut positivity for beta-hCG. The remaining oncofetal markers applied (PLAP and alpha1-fetoprotein) were negative. Electron microscopy demonstrated the presence of numerous nuclear pockets and the lack of intercellular junctions. DNA analysis by polymerase chain reaction showed clonal rearrangement of Ig heavy-chain genes. The patient responded promptly to the administration of MACOP-B. To the best of our knowledge, this is the first example of B-cell lymphoma showing positivity for beta-hCG; a similar aberrant expression was previously observed only in three Japanese patients with human T-cell lymphotropic virus type I+ adult T-cell lymphoma/leukemia. Because primary mediastinal large B-cell lymphoma has in the past been frequently confused with germ cell tumors, pathologists should be aware of possible beta-hCG expression by lymphomatous cells to avoid the risk of misdiagnosis.

Adult↗
PubMed1999

Alarm communication network to help carers of the elderly for safety purposes: a survey of a project.

Over years, radical changes in engineering technology have taken place due to greatly improved instrumentation, enhanced computing power, new sensors and upgraded transmission mediums making it possible to achieve in the field what once could only be done on laboratory models. In daily life, the use of an active self-testing instrumentation endowed with a self-diagnostic capability built into the structural fabric of a machine permits us to monitor the initiation of breakdown, corrosion and erosion. This has become particularly important in such means of transportation as planes, boats and automobiles where advanced instrumentation, signal processing and pattern recognition systems operate in fairly conventional structures. By capitalizing on the technological progress in the field of instrumentation and data processing, help can be contemplated for elderly people in nursing homes through detection of abnormal situations. The continued assistance to elderly people is achieved by utilizing a technological system respectful of the elderly's privacy and operating without their active participation.

Activities of Daily Living↗
PubMed1999

Expression of beta-integrin adhesion molecules in non-Hodgkin's lymphoma: correlation with clinical and evolutive features.

PURPOSE: To analyze beta-integrin expression in non-Hodgkin's lymphomas (NHLs) in order to assess its distribution among histologic subtypes and correlate with clinical features and outcome. PATIENTS AND METHODS: The expression of alpha2 through alpha6 and beta1 common chains of very late activation antigen (VLA ) molecules and alphaL (CD11a) and beta2 common (CD18) chains of leukocyte function-associated antigen 1 molecule were studied in 137 patients with NHL. Immunostaining was performed by a streptavidin-biotin alkaline phosphatase method, and integrin expression was semiquantitatively assessed. Correlation with clinical features was analyzed in 80 patients consecutively diagnosed as having immunocytoma (five cases), follicular lymphoma (19 cases), mantle-cell lymphoma (MCL; four cases), diffuse large-cell lymphoma (DLCL; 40 cases), lymphoblastic lymphoma (LL; six cases), anaplastic Ki-1-positive lymphoma (one case), and other peripheral T-cell lymphoma (five cases). RESULTS: MCL cells did not show alpha2 and alpha6 expression, whereas most expressed weak to moderate levels of alpha3, alpha4, and alpha5. LL mostly showed alpha2 to alpha5 expression, whereas alpha6 was observed in seven of 11 cases (higher proportion than that shown in other subgroups). Alpha chains of VLA molecules were present more frequently in T-cell than in B-cell lymphomas. Patients with moderate/strong alpha4, CD11a, and beta2 common chain expression presented more frequently with advanced stage and bone marrow infiltration. Moderate/strong alpha4, alpha5, and beta1 common chain expression correlated with extranodal involvement. In the subset of B-cell DLCL patients, negative/weak expression of alpha3 and alpha4 chains was related to a higher complete response rate. Moreover, negative or weak expression of alpha2, alpha3, alpha4, and beta1( )common chain had favorable significance for overall and failure-free survivals. CONCLUSION: In NHL, beta-integrin expression is related to histologic subtype. The expression pattern of these molecules probably influences disease dissemination and patients' prognoses.

CD18 Antigens↗
PubMed1999

Mantle-cell lymphoma.

Mantle-cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive pregerminal center cells characterized by a nodular or diffuse proliferation of atypical lymphoid cells with a monoclonal B-cell phenotype and coexpression of CD5. Two cytologic variants have been identified, typical and blastic. Typical cases show a proliferation of small to intermediately sized lymphoid cells with irregular nuclei and scarce cytoplasm. Blastic variants include a spectrum of intermediate to large cells with round or irregular nuclei and finely dispersed chromatin. These cases have a higher proliferative activity and a more aggressive clinical evolution. MCL is genetically characterized by 11q13 translocations and bcl-1 rearrangement. This alteration leads to a constant overexpression of cyclin D1, which plays an important pathogenetic role, probably deregulating cell-cycle control by overcoming the suppressor effect of retinoblastoma protein (Rb) and p27Kip1. Detection of cyclin D1 may be used as a highly specific marker of MCL because it is expressed in virtually all of these tumors, but in only a few reported cases of aggressive variants of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and a small percentage of cases of multiple myeloma. Aggressive variants have additional genetic alterations, including inactivation of p53 and p16INK4a tumor-suppressor genes. Clinically, MCL presents in elderly males with advanced disease and frequent extranodal involvement, particularly with involvement of bone marrow, gastrointestinal tract, and spleen. The clinical evolution is relatively aggressive, with poor response to conventional therapeutic regimens and a median survival duration of 3 to 4 years. Further studies are needed to define better new therapeutic strategies for the management of these patients.

Chromosomes, Human, Pair 11↗
PubMed1998

p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas.

The molecular mechanisms underlying the pathogenesis of aggressive lymphomas and the histological transformation of indolent variants are not well known. To determine the role of p16(INK4a) gene alterations in the pathogenesis of non-Hodgkin's lymphomas (NHLs) and the histological progression of indolent variants, we have analyzed the expression, deletions, and mutations of this gene in a series of 112 NHLs. Hypermethylation of the gene was also examined in a subset of tumors with lack of protein expression but without mutations or deletions of the gene. p16(INK4a) gene alterations were detected in 3 out of 64 (5%) indolent lymphomas but in 16 out of 48 (33%) primary or transformed aggressive variants. In the low-grade tumors, p16(INK4a) alterations were detected in 1 (4%) chronic lymphocytic leukemia (hemizygous missense mutation), 1 (6%) follicular lymphoma (homozygous deletion), and 1 (5%) typical mantle cell lymphoma (homozygous deletion). The two later cases followed an aggressive clinical evolution. In the aggressive tumors, p16(INK4a) gene alterations were observed in 2 (29%) Richter's syndromes (2 homozygous deletions), 3 (33%) transformed follicular lymphomas (1 homozygous deletion and 2 nonsense mutations), 3 (43%) blastoid mantle cell lymphomas (2 homozygous and 1 hemizygous deletions), 5 (28%) de novo large-cell lymphomas (1 homozygous deletion and 4 hypermethylations), 2 lymphoblastic lymphomas (2 homozygous deletions), and 1 of 2 anaplastic large cell lymphomas (hypermethylation). Protein expression was lost in all tumors with p16(INK4a) alterations except in the typical chronic lymphocytic leukemia (CLL) with hemizygous point mutation. Sequential samples of the indolent and transformed phase of three cases showed the presence of p16(INK4a) deletions in the Richter's syndrome but not in the CLL component of two cases, whereas in a follicular lymphoma the deletion was present in both the follicular tumor and in the diffuse large-cell lymphoma. In conclusion, these findings indicate that p16(INK4a) gene alterations are a relatively infrequent phenomenon in NHLs. However, deletions, mutations, and hypermethylation of the gene with loss of protein expression are associated with aggressive tumors and they may also participate in the histological progression of indolent lymphomas.

Cell Transformation, Neoplastic↗
PubMed1998

Cathepsin L2, a novel human cysteine proteinase produced by breast and colorectal carcinomas.

We have identified and cloned a new member of the papain family of cysteine proteinases from a human brain cDNA library. The isolated cDNA codes for a polypeptide of 334 amino acids that exhibits all of the structural features characteristic of cysteine proteinases, including the active site cysteine residue essential for peptide hydrolysis. Pairwise comparisons of this amino acid sequence with the remaining human cysteine proteinases identified to date showed a high percentage of identity (78%) with cathepsin L; the percentage of identity with all other members of the family was much lower (<40%). On the basis of these structural characteristics, we have tentatively called this novel protein cathepsin L2. The cDNA encoding the mature cathepsin L2 was expressed in Escherichia coli, and after purification, the recombinant protein was able to degrade the synthetic peptide benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methylcoumarin, which is commonly used as a substrate for cysteine proteinases. Cathepsin L2 proteolytic activity on this substrate was abolished by trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane, an inhibitor of cysteine proteinases, thus providing additional evidence that the isolated cDNA encodes a functional cysteine proteinase. Northern blot analysis of polyadenylated RNAs isolated from a variety of human tissues demonstrated that cathepsin L2 is predominantly expressed in the thymus and testis. This finding is in marked contrast with the wide tissue distribution of most cysteine proteinases characterized to date, including cathepsin L, and suggests that cathepsin L2 may play a specialized role in the thymus and testis. Expression analysis of cathepsin L2 in human tumors revealed a widespread expression in colorectal and breast carcinomas but not in normal colon or mammary gland or in peritumoral tissues. Cathepsin L2 was also expressed by colorectal and breast cancer cell lines as well as by some tumors of diverse origin, including ovarian and renal carcinomas. These results open the possibility that this novel enzyme may be involved in tumor processes, as already reported for other cysteine proteinases, including cathepsin L.

Amino Acid Sequence↗
PubMed1998

cdc25 cell cycle-activating phosphatases and c-myc expression in human non-Hodgkin's lymphomas.

cdc25A, cdc25B, and cdc25C are a family of human phosphatases that activate the cyclin-dependent kinases at different points of the cell cycle. cdc25A and cdc25B have been shown to have oncogenic potential, and they have been identified as transcriptional targets of c-myc. To determine the role of cdc25 genes in the pathogenesis of human lymphomas and their possible correlation with c-myc deregulation, we have analyzed the expression of cdc25A, cdc25B, and cdc25C and c-myc genes in a series of 63 non-Hodgkin's lymphomas and 8 nonneoplastic lymphoid tissues. The mRNA levels of the three phosphatases in the nonneoplastic tissues were negative or negligible. cdc25B overexpression was detected in 35 tumors (56%). This overexpression was more frequently found in aggressive (81%) than in indolent lymphomas (36%; P < 0.01). cdc25B overexpression was also significantly associated with a higher proliferative activity of the tumors. No cdc25B gene amplification or rearrangements were detected by Southern blot analysis. A biallelic EcoRI polymorphism of cdc25B gene was identified with a similar distribution in patients with lymphoma and in a normal population. cdc25A was overexpressed in three aggressive lymphomas. No detectable cdc25C mRNA levels were seen in any of the tumors. c-myc was overexpressed in 43% of tumors, and it correlated significantly with the presence of cdc25B up-regulation. Twenty-six of 35 (74%) lymphomas with high levels of cdc25B mRNA also showed c-myc overexpression, whereas 27 of 28 (96%) tumors without detectable or with very low cdc25B expression also had undetectable c-myc levels (P < 0.0001). In addition, a significant linear correlation was found between the cdc25B and c-myc mRNA levels (r = 0.575, P < 0.001). These findings suggest that cdc25B overexpression in non-Hodkin's lymphoma may participate in the pathogenesis of aggressive variants, and it may cooperate with c-myc oncogene in the development of these tumors.

Blotting, Northern↗
PubMed1998

Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors.

BACKGROUND: The goal of this study was to analyze the presenting features, natural history, and prognostic factors in 59 patients with well characterized mantle cell lymphoma (MCL). METHODS: Cases were classified as nodular or diffuse and as typical or blastic variants. Age, performance status (PS), histologic variants, mitotic index (MI), hematologic parameters, tumor extension data, and International Prognostic Index (IPI) were recorded and evaluated for prognosis. RESULTS: The median age of the patients was 63 years (range, 39-83 years), and the male to female ratio was 3:1. Fifty-three patients had typical histology (3 nodular and 50 diffuse), and 6 had the blastic variant. Approximately 95% of patients presented with advanced stage disease (Ann Arbor Stage III-IV). Leukemic expression was observed in 58%. Complete and partial response rates were 19% and 46%, respectively. Parameters associated with lower response rate were Stage IV, high/intermediate or high risk IPI, and increased lactate dehydrogenase (LDH) level. In the logistic regression analysis, high LDH level and Stage IV disease were associated independently with lower response rate. Median survival was 49 months. Parameters associated with a short survival were: poor PS, splenomegaly, B-symptoms, MI > 2.5, leukocyte count > 10 x 10(9)/L, high LDH level, blastic variant, and high/intermediate or high risk IPI. In the Cox proportional hazards regression model, only poor PS (relative risk [RR] = 3.3; P = 0.002), splenomegaly (RR = 2.8; P = 0.007), and MI > 2.5 (RR = 2.4; P = 0.012) were associated with short survival. CONCLUSIONS: In this series, patients with MCL presented with advanced stage and extranodal involvement. Only a minority of patients achieved a complete response. The median survival was 4 years, with PS, splenomegaly, and MI being the most important factors predicting survival. These results show clearly that more effective therapies for MCL are needed.

Adult↗
PubMed1998

p21WAF1/Cip1 is associated with cyclin D1CCND1 expression and tubular differentiation but is independent of p53 overexpression in human breast carcinoma.

p21WAF1/Cip1 is an inhibitor of cdk/cyclin complexes, and thus regulates the cell cycle. p21 is also related to cell differentiation and is regulated by wild-type p53, although p53-independent regulatory pathways have been proposed. In order to analyse p21 expression as well as its relationship with p53 in human breast cancer, an immunohistochemical analysis was undertaken of 77 breast carcinomas, 16 of them with an in situ component; 30 adjacent normal tissue samples; and five non-neoplastic specimens. Forty-four infiltrating carcinomas (57 per cent) were p21-positive. Expression of p21 was also observed in pre-invasive lesions, whereas normal ducts were negative or focally and weakly positive. p21 expression was associated with high histological grade (II + III) (P = 0.017) and poor tubule formation (P = 0.002), and was significantly less frequent in lobular carcinomas (P = 0.0001). p21 positivity also correlated with increased proliferation, but this seemed to be dependent on the histological grade. Twenty carcinomas (26 per cent) showed p53 overexpression, but this was not associated with p21 negativity, suggesting the existence of p53-independent mechanisms for p21 regulation in vivo. Cyclin D1CCND1 expression was analysed in the same series and an association between p21 and cyclin D1 expression was found, since 23 of 26 cyclin D1-positive carcinomas were p21-positive (P < 0.001 ...). In conclusion, p21 is frequently overexpressed in breast carcinomas and this occurs in the early stages of neoplastic progression. This overexpression seems to be independent of p53 status and might be involved in cyclin D1 modulation.

Blotting, Western↗
PubMed1998

Collagenase-3 expression is associated with advanced local invasion in human squamous cell carcinomas of the larynx.

Collagenase-3 (MMP-13) is a matrix metalloproteinase recently identified on the basis of differential expression in normal breast tissues and in breast carcinoma. To date, collagenase-3 expression has been reported only in breast carcinomas and in articular cartilage of arthritic patients; the presence and possible implication of this enzyme in the progression of other malignant tumours are unknown. In this study collagenase-3 mRNA expression has been analysed by northern blot in a series of 35 matched squamous cell carcinomas of the larynx and the corresponding adjacent non-neoplastic tissues. In addition, mRNA expression of membrane type 1-matrix metalloproteinase (MT1-MMP) and gelatinase A, two matrix metalloproteinases which have the ability to activate collagenase-3 in vitro, was also examined in the same cases. No collagenase-3 expression was detected in any of the 35 normal mucosae, but collagenase-3 mRNA was observed in 20 of the 35 carcinomas (57 per cent). Western blot analysis revealed the presence of collagenase-3 protein in those carcinomas with high levels of mRNA expression, whereas no protein was detected in the carcinomas with negative mRNA expression, or in any of the normal tissues. The protein was localized predominantly in tumour epithelial cells. Collagenase-3 expression correlated significantly with better histological differentiation of the tumours (p = 0.026), as well as with advanced local invasion (p = 0.026). Collagenase-3 upregulation was also significantly associated with MT1-MMP and gelatinase A overexpression. These findings suggest that collagenase-3 expression may contribute to the progression of a significant subset of squamous cell carcinomas of the larynx and that its coordinate overexpression with MT1-MMP and gelatinase A may have a cooperative effect in the progression of the tumours.

Adult↗
PubMed1998

Ki-ras gene mutations and absence of p53 gene mutations in spontaneous and urethane-induced early lung lesions in CBA/J mice.

Ki-ras and p53 genes are involved in human lung carcinogenesis; however, the role of these genes in experimental lung tumors is not well known. In our study, the CBA/J mouse strain was used to investigate the presence of Ki-ras and p53 alterations in lung carcinogenesis of spontaneous tumors and tumors induced with high and low doses of urethane (ethyl carbamate). To study the presence of these alterations in the early stages of lung carcinogenesis and in very small lung tumors, restriction fragment length polymorphism and single-strand conformation polymorphism analyses were performed on polymerase chain reaction-amplified DNA from microdissected tumoral and normal lung samples. Ki-ras gene mutations in codons 12 and 61 were detected in all types of lung lesions, even in small and preneoplastic lesions, and their incidence increased with progression from lung hyperplasias (18%) to adenomas (75%) and to carcinomas (80%). Urethane exposure, in both high and low doses, increased the incidence of Ki-ras mutations in lung tumors, especially in adenomas. The presence of Ki-ras gene mutations in very small urethane-induced lung tumors and the absence of hyperplasias among the treated-group lesions may indicate that urethane accelerates tumoral progression. No p53 mutations were detected in exons 5-8 in any of the epithelium-derived lung tumors. Only one p53 mutation in exon 5 was found in a spontaneous lymphoma. Therefore, p53 mutations do not seem to cooperate with Ki-ras gene mutations or represent an alternative molecular pathway in murine carcinogenesis.

Adenoma↗
PubMed1998

Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor.

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27Kip1 expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27Kip1 gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin's lymphoma other than MCL, p27Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27Kip1 gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27Kip1 expression with the proliferation rate. This peculiar uncoupling of p27Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.

Blotting, Southern↗
PubMed1998

Blastic variant of mantle cell lymphoma shows a heterogenous pattern of somatic mutations of the rearranged immunoglobulin heavy chain variable genes.

Mantle cell lymphoma is a distinct clinicopathological entity associated with t(11;14) and cyclin D1 overexpression. The majority of cases show uniform morphological and phenotypic features characterized by a monotonous proliferation of small-to-medium-sized irregular B cells that express CD5 and bright surface immunoglobulin IgM and IgD. By sequence analysis of the rearranged immunoglobulin heavy chain variable genes (VH), it has been shown that these lymphoma cells carry little if no somatic mutations, as described for the fetal CD5+ cells or B1 cells. Besides mantle cell lymphoma with classic histological features, a morphological variant of mantle cell lymphoma with blastic features and a more aggressive clinical course has been described. To investigate whether this variant is closely related, by the cell of origin, to typical cases, we analysed the presence and the pattern of somatic mutations of the VH genes in a series of nine cases diagnosed as such. Our cases of blastic mantle cell lymphomas rearrange most frequently VH4 and VH3 family genes. In three cases there was a complete homology to published germline genes, and a near complete homology was documented in another three. In contrast, the remaining three cases showed somatic mutations in their rearranged VH genes. Mutation analysis revealed evidence for antigen selection in one of these three cases. Taken together, these data are similar to those of normal adult-type B1 cells and those described for chronic lymphocytic leukaemia (CLL) but slightly different to those reported for classic mantle cell lymphoma. It is likely that blastic mantle cell lymphoma as well as CLL originates from adult-type B1 cells. More cases will need to be studied to determine whether classic mantle cell lymphoma is different from the blastic subtype and if it arises from fetal-type B1 cells.

Amino Acid Sequence↗