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B Czepulkowski

Publications and source records attributed to B Czepulkowski.

At least 19 recordsLinked to original sources
PubMed2003

Epstein-Barr virus-related post-transplant lymphoproliferative disorder with t(9;14)(p11-12;q32).

The immunoglobulin heavy chain gene locus on 14q32 is known to be involved in translocations that are associated with B-lymphoproliferative disorders, typically Burkitt lymphoma and B-cell acute lymphoblastic leukemia. Several cytogenetic abnormalities have been described in post-transplant lymphoproliferatve disease (PTLD), some of which include this locus. To our knowledge, we report the first case of translocation t(9;14)(p11-12;q32) in a PTLD that developed after orthoptic liver transplantation.

Biliary Atresia↗
PubMed2003

Mosaic trisomy 2 in myelodysplastic syndromes and acute myeloblastic leukemias.

We present a short report here of two more patients with trisomy 2 as the sole chromosomal abnormality in a hematologic malignancy. Although trisomy 2 is a recognized abnormality in neoplasms, particularly hepatoblastomas, to the best of our knowledge only three other cases have been reported with trisomy 2, in patients with a hematologic malignancy. The two cases presented here of myelodysplastic syndrome transforming to acute myeloblastic leukemia and chronic myelomonocytic leukemia showed trisomy 2 as the sole abnormality.

Aged↗
PubMed2002

Frequent expression of HAGE in presentation chronic myeloid leukaemias.

Cancer testis (CT) antigens provide attractive targets for cancer-specific immunotherapy. Although CT genes are expressed in some normal tissues, such as the testis and in some cases placenta, these immunologically protected sites lack MHC I expression and as such, do not present 'self' antigens to T cells. To date, CT genes have been shown to be expressed in a range of solid tumours, but rarely in haematological malignancies. We have extended previous studies to investigate the expression of a comprehensive range of CT genes (MAGE-A1, -A3, -A6, -A12, BAGE, GAGE, HAGE,LAGE-1, NY-ESO-1 and RAGE) for their expression in a cohort of acute and chronic myeloid leukaemia patient samples. CT expression was not detected in 20 normal bone marrow or peripheral blood stem cell samples. In acute myeloid leukaemia (AML) nine of the 26 (35%) samples analysed expressed one or more of the CT genes with six of the samples (23%) expressing HAGE. In chronic myeloid leukaemia (CML) 24 of 42 (57%) presentation chronic myeloid leukaemia (CML) patient samples expressed one or more CT antigen with 23 expressing HAGE. We have shown that HAGE is frequently expressed in CML, and to a lesser extent in AML patient samples. This is the first demonstration of HAGE gene expression in myeloid leukaemia patients and the frequent expression of HAGE at disease presentation opens up the possibility of early immunotherapeutic treatments.

Adolescent↗
PubMed2002

Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sézary syndrome and mycosis fungoides.

BACKGROUND: Data on genome-wide surveys for chromosome aberrations in primary cutaneous T-cell lymphoma (CTCL) are limited. OBJECTIVE: To investigate genetic aberrations in CTCL. METHODS: We analysed 18 cases of Sézary syndrome (SS) and 16 cases of mycosis fungoides (MF) by comparative genomic hybridization (CGH) analysis, and correlated findings with the results of additional conventional cytogenetics, fluorescent in situ hybridization (FISH) and allelotyping studies. RESULTS: CGH analysis showed chromosome imbalances (CIs) in 19 of 34 CTCL cases (56%). The mean +/- SD number of CIs per sample was 1.8 +/- 2.4, with losses (1.2 +/- 2.0) slightly more frequent than gains (0.6 +/- 1.0). The most frequent losses involved chromosomes 1p (38%), 17p (21%), 10q/10 (15%) and 19 (15%), with minimal regions of deletion at 1p31p36 and 10q26. The commonly detected chromosomal gains involved 4/4q (18%), 18 (15%) and 17q/17 (12%). Both SS and late stages of MF showed a similar pattern of CIs, but no chromosomal changes were found in three patients with T1 stage MF. Of the 18 SS cases also analysed by cytogenetics, seven showed clonal chromosome abnormalities (39%). Five cases had structural aberrations affecting chromosomes 10 and 17, four demonstrated rearrangement of 1p and three revealed an abnormality of either 6q or 14q consistent with CGH findings. FISH analysis showed chromosome 1p and 17q rearrangements in five of 15 SS cases, and chromosome 10 abnormalities in four SS cases consistent with both the G-banded karyotype and the CGH results. In addition, allelotyping analysis of 33 MF patients using chromosome 1 markers suggested minimal regions of deletion at D1S228 (1p36), D1S2766 (1p22) and D1S397 (1q25). CONCLUSIONS: These findings provide a comprehensive assessment of genetic abnormalities in CTCL and a rational approach for further studies.

Chromosome Aberrations↗
PubMed2001

A case of adult T-cell leukaemia/lymphoma characterized by multiplex-fluorescence in situ hybridization, comparative genomic hybridization, fluorescence in situ hybridization and cytogenetics.

Adult T-cell leukaemia/lymphoma (ATLL) is a neoplasm of mature helper (CD4) T lymphocytes. Little is known, however, about the chromosome aberrations associated with the pathogenesis of this malignancy. Using molecular cytogenetic techniques we, therefore, investigated a 44-year-old man who had a 7-year history of ATLL with cutaneous involvement mimicking primary cutaneous T-cell lymphoma. Conventional cytogenetics revealed gross chromosomal changes with chromosome numbers ranging from 71 to 82. There were structural abnormalities of chromosomes 7 and 9, partial deletions of chromosomes 1, 3, 5 and 6, and loss of chromosomes 2, 4, 9, 11--14, 21 and 22. Multiplex-fluorescence in situ hybridization (M-FISH) identified two derivative chromosomes, der(6)t(6;7)(q16;q21) and der(7)t(6;7)(q16;q21)ins(6;12)(q2?;?), and a deletion of chromosome 1p. Conventional FISH confirmed the M-FISH findings. Comparative genomic hybridization of the blood revealed gains of DNA copy number at 1q12--25, 6p24--25, 9p23, 16p13--q13, 17q11--21, 19p13 and 20q13 and loss at 11p15 while lymph nodes showed gains at 3p22--24, 3q27--29, 7q36 and 15q26 and losses at 2p24--25, 2q37, 10p14--15, 11p15, 13q33--34 and 16p13.3. No DNA copy number changes were seen in a skin lesion. These results show the extent of genetic abnormalities within this malignancy.

Adult↗
PubMed1999

Delineation of multiple deleted regions in 7q in myeloid disorders.

Loss of chromosome material due to deletions of the long arm of chromosome 7, del(7q), is a consistent finding in all types of myeloid disorders, invariably associated with a poor prognosis. Two different segments, 7q22 and 7q32-q33, have been implicated as critical regions of gene loss associated with these disorders. In the present study, we used fluorescence in situ hybridization (FISH) to characterize the 7q22 breakpoint of an apparently balanced t(7;7)(p13;q22) in an acute myeloid leukemia patient. FISH analysis on bone marrow metaphases from this patient revealed that the sequence corresponding to a series of three ordered cosmids from 7q22 was deleted from one of the der(7) chromosomes. These cosmids contain the human homologue of the Drosophila homeobox gene cut (CUTL1) and span a region of approximately 150 kb. Although the proximal boundary of the deleted segment could not be exactly defined, we estimate the size of this deletion to be approximately 500 kb. Subsequently, we carried out FISH studies using the CUTL1 cosmids on a further 16 patients with deletions of 7q and myeloid disorders. The sequence corresponding to at least two of the cosmids was deleted from the del(7q) in 11 out of 14 cases with a proximal breakpoint within 7q22. Further detailed FISH mapping in this series of 17 patients has identified two other nonoverlapping commonly deleted segments at 7q31-q32 and 7q33, respectively. These data confirm and refine other studies, implying that several different genes on 7q may be involved in the pathogenesis of myeloid diseases. Genes Chromosomes Cancer 25:384-392, 1999.

Adult↗
PubMed1998

'Low-risk' myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins.

We performed flow cytometric analysis of CD34+ cell apoptosis in 59 patients with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) secondary to MDS (MDS-AML) using annexin V-FITC, which binds to exposed phosphatidylserine on apoptotic cells. Apoptosis was significantly increased in FAB subtypes RA, RARS and RAEB (<10% blasts) (56.5% (15.1-86.5%)) compared to normal controls (18.5% (3.4-33.4%), P<0.0001) and RAEB-t/MDS-AML (16% (2.1-43.2%), P<0.0001). There was no correlation between % apoptosis, Full blood count or cytogenetics in any disease category. Two-colour cytometric analysis of permeabilized CD34+ cells stained with antibodies to Bcl-2, Bcl-X (anti-apoptotic), Bax and Bad (pro-apoptotic), demonstrated significantly higher ratios of pro- v anti-apoptotic proteins in early MDS (2.47 (1.19-9.42) compared to advanced disease (1.14 (0.06-3.32), P=0.0001). Moreover, using repeated measures of variants (ANOVA), we found that variations between individual Bcl-2-related proteins differed significantly according to disease subtype (P<0.0005). Our results confirm that CD34+ cell apoptosis was significantly increased in MDS subtypes RA and RARS and fell with disease progression. Early MDS was also associated with a significantly higher CD34+ cell pro- v anti-apoptotic Bcl-2-family-protein ratio than advanced disease. Furthermore, patterns of expression of individual Bcl-2 related proteins differed significantly between different disease categories. However, no correlation between pro- v anti-apoptotic Bcl-2-family-protein ratios and the degree of apoptosis was observed.

Acute Disease↗
PubMed1997

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia.

Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy (de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (< 5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.

Acute Disease↗
PubMed1996

Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML).

The genes for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) are located within regions subject to non-random chromosomal abnormalities in the myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Acetylcholinesterase is mapped to 7q22, within the critical deleted region presumed to contain a myeloid specific tumour suppressor gene. Butyrylcholinesterase is mapped to 3q26: abnormalities at this region are associated with sub-types of MDS and AML with thrombocytopenia, or with increased platelet counts. Both ACHE and BCHE have been implicated as playing a role in megakaryopoiesis and thrombopoiesis, and these genes have been observed to be co-amplified in acute myeloid leukaemia. Recent findings suggest a more significant role for the ACHE gene in haemopoiesis by regulating multipotent stem cell proliferation, and apoptosis in cells undergoing erythroid and myeloid differentiation. This led us to investigate gene copy-number alterations at these genes in MDS and AML. Samples were screened by slot-blot hybridization, and if changes were observed, by Southern blotting. A total of 42 samples from 31 de novo AML patients, 10 samples from eight cases of post-MDS AML and 85 samples from 67 MDS patients were analysed with probes for ACHE, BCHE, c-MYC, MDR-1 and globin control. Changes in ACHE and/or BCHE were observed in 9/31 de novo AML patients, and in 7/67 MDS patients: 1/37 cases of refractory anaemia (RA), 1/10 cases of refractory anaemia with excess blasts (RAEB) and 5/20 chronic myelomonocytic leukaemia (CMML) patients. The amplification events observed generated copy numbers no greater than 10, showed normal restriction patterns and had no clear correlation with megakaryopoiesis or thrombopoiesis. Loss of signal at the ACHE locus was observed: haploid signal intensity was seen in seven samples: one RA with thrombocytopenia, three CMML, one AML-M5a (no karyotypic abnormalities of chromosome 7), one AML-M4 (monosomy 7), and one case of AML-M7 (karyotype unknown). Homozygous deletion was observed at relapse of an additional patient with AML-M4. These data reinforce the possibility that ACHE may play a role as a myeloid tumour suppressor gene.

Acetylcholinesterase↗
PubMed1996

Myelosuppressive chemotherapy to mobilize normal stem cells in chronic myeloid leukemia.

Ten patients with Ph+ chronic myeloid leukemia (CML) were treated with idarubicin, cytarabine and etoposide followed by G-CSF to harvest Ph-negative progenitor cells. Six were in first chronic phase (CP1), and four beyond CP1. Between two and six aphereses (median 3, total 36) were performed starting 9-26 days (median 14.5) after chemotherapy when the leukocyte count was 0.6-4.7 x 10(9)/l (median 1.2). 1.3-3.6 x 10(8) mononuclear cells/kg (median 2.8), 0-128.4 x 10(4) CFU-GM/kg (median 1.2; seven patients) and 0.3-25.1 x 10(6) CD34+ cells/kg (median 9.8; seven patients) were collected. Seven of 27 harvests showing metaphases were 100% Ph-negative, 11 partially Ph-negative, and nine were 100% Ph+. All three patients with 100% Ph-negative collections were in CP1 and within 4-26 months of diagnosis. Four of six CP1 patients showed significant cytogenetic response compared with none of four beyond CP1 (P = 0.036). The absolute neutrophil count remained < 0.5 x 10(9)/l for 9-44 days (median 15.5) following chemotherapy. Four patients (three Ph-negative) were autografted after 16 mg/kg busulfan (n = 2) or 200 mg/m2 melphalan (n = 2). One of the three patients receiving Ph-negative cells died of graft failure, and two are alive with 15% and 50% Ph-negative cells at 15 and 11 months on interferon-alpha. We conclude that it is possible to harvest Ph-negative cells after myelosuppressive chemotherapy in some CML patients treated early in the course of CP1. However, in view of lack of consistent response, investigation of alternative approaches is necessary.

Adolescent↗
PubMed1993

Consistent interstitial chromosomal deletions in myeloid malignancies and their correlation with fragile sites.

Chromosomal deletions occurring in myeloid malignancies have sometimes been reported either with no breakpoints or as terminal deletions. It is of importance to deduce whether these deletions are actually terminal or interstitial because this has implications for their biologic consequences and the mechanism of their development. Chromosomal deletions have been observed in 38 patients with myeloid malignancies. Two or more deletions occurred in six cases, and in seven cases this was part of a complex abnormality. In all, 45 deletions were observed. In all cases analyzed, the deletions consistently were interstitial. Of the 38 cases, 16 were myelodysplastic syndromes (MDS) [refractory anemia (RA), three; RA with ringed sideroblasts (RARS) three; RA with excess of blasts (RAEB) eight; RAEB in transformation (RAEB-t) one; and unclassified, one], 11 cases were acute nonlymphocytic leukemia (ANLL), and 11 were other myeloproliferative disorders [polycythemia rubra vera (PRV) seven; essential thrombocytopenia (ET), three; unclassified, one]. In general, no uniformity of breakpoints could be identified other than del(9)(q13q22.2) most of which occurred with t(8;21) and del(20)(q11.2q13.3 or 13.1). The breakpoints corresponded to or were adjacent to fragile sites in 49% (proximal 64%, distal 33%). These data emphasize that chromosomal deletions in myeloid malignancies are interstitial. The uniformity of breakpoints in del 9q and del 20q supports the concept that in some instances the exact breakpoints may be important through juxtaposition of genes rather than loss of critical regions. The data also suggest that there may be different mechanisms for the development of proximal and distal breakpoints.

Adult↗
PubMed1989

Partial deletion 8q without Langer-Giedion syndrome: a recognisable syndrome.

We report two de novo cases of del(8)(pter----q24.1:) with breakpoints involving the distal part of band 8q24.1. The clinical features were similar and there were no obvious stigmata of Langer-Giedion syndrome (LGS). There are three other cases reported with a deletion of chromosome 8 at approximately the same breakpoint, one without LGS and some similarities to our cases, the other two with LGS. Our findings would support the observation that the critical segment for the assignment of LGS is proximal to or involves the proximal part of 8q24.1, but a review of published reports suggests that the aetiology of LGS may be a more complex issue.

Chromosome Deletion↗
PubMed1989

Three infants having null acute lymphoblastic leukemia with chromosome rearrangements at 11q23: no involvement of a heritable fragile site in this band.

Three families are presented in which an infant with null acute lymphoblastic leukemia had a karyotype rearrangement involving a break at 11q23. Peripheral blood was obtained, where possible, from both parents and from the child during periods of remission. The blood was stimulated with phytohemagglutinin and cultured under conditions that enhance expression of heritable folate-sensitive fragile sites. In all individuals studied very low levels of fra(11)(q23.3) were observed. These levels were far below those recorded for expression of the heritable folate-sensitive site fra(11)(q23.3) but are comparable with expression of the common fragile site fra(11)(q23.3) under these conditions.

Chromosome Banding↗
PubMed1988

Childhood monosomy 7 revisited.

Monosomy 7 is found in acute myeloid leukaemia (AML) and myelodysplasia and is characteristic of a rare chronic myeloproliferative disease (MPD) of young children. We have seen 16 children with monosomy 7. Their clinical features and response to treatment are discussed. Monosomy 7 diseases appear to have a particularly poor prognosis. The AML is often resistant to treatment and relapse is common. Children with chronic MPD die of bone marrow failure or evolve to AML or myelofibrosis. We have treated these children intensively with combination chemotherapy and allogeneic bone marrow transplantation. Four children with MPD received supportive care and low dose chemotherapy alone. They all died, surviving between 4 months and 4 years. Six children with MPD received intensive chemotherapy: three remitted, one relapsing after 9 months, the others remaining in remission at 18 months and 3 years. One child with MPD has undergone successful BMT and survives 7 1/2 years after presentation. Remission was achieved in three of four cases of AML. They all relapsed within 9 months. Bone marrow transplantation was successful in one child with myelofibrosis. Intensive chemotherapy and early bone marrow transplantation is likely to offer these children their best chance of survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Cellular and molecular studies on infant null acute lymphoblastic leukemia.

We have studied the cellular and molecular basis of eight cases of infant null acute lymphoblastic leukemia (ALL). All eight patients were under 9 months of age and presented with leukocyte counts in excess of 60 X 10(9)/L, organomegaly, and in two cases CNS infiltration. Although seven cases were morphologically classified as ALL, one patient had both lymphoid and myeloid features. Phenotypic analysis of leukemic blasts from all patients showed a typical null ALL pattern, ie, CD10 (common ALL antigen)-negative, strongly HLA-DR-positive, and CD19 (B4)-positive. The presence of terminal deoxynucleotidyl transferase (TdT) at presentation was positive in six patients' cells and negative in two. Two patients also expressed the myeloid-associated markers CD33 (MY9) and CD15 (TG1), and coexpression of CD19 and CD33 was confirmed in these two by using dual marker flow cytometry (fluorescence-activated cell sorting). Electron microscopic examination of the same two patients' cells showed the presence of monocytoid blasts that labeled with the pan-B cell antibody B4 (CD19). Short-term culture of one of these patients cells in the presence of phorbol ester resulted in the majority of the cells exhibiting myeloid markers, strong nonspecific esterase positivity, and phagocytic properties. Cytogenetic analysis showed the common feature in 7 of 8 cases to be a break in band 11q23. Molecular analysis of DNA from the blast cells of all eight patients showed rearrangement of the immunoglobulin heavy-chain genes in all cases without, however, any evidence of kappa light-chain rearrangement. T cell receptor genes were present in the germline configuration in all cases. Rearrangements of the c-ets 1 oncogene, which maps to band 11q23, were not detected, thus providing no evidence for involvement of this oncogene in the common disease process. Our data indicate that although infant null ALL may present as a heterogeneous disease the similarity of many features between cases suggests a common derivation from a precursor cell sharing phenotypic and genotypic features of both B and myeloid progenitor cells.

Antigens, Neoplasm↗
PubMed1987

Duplication of one of the products of the t(8;21) translocation in a patient with refractory anemia with excess blasts in transformation.

A 34-year-old man with refractory anemia with excess blasts in transformation is reported, having a t(8;21) translocation and a duplication of one of the products, der(21). The duplicated product had not been observed at presentation in malignant disease, as far as we are aware; thus, the findings are discussed with regard to this case and other possible smoldering leukemias. The diagnostic use of cytogenetics is also considered.

Adult↗
PubMed1987

Subtle abnormalities in the short arm of chromosome 11 in acute myeloid leukemia.

A series of four patients with small deletions of the short arm of chromosome #11 is presented. In two of these patients, deletion of 11p was the sole karyotypic abnormality. When compared with similar reported cases an association with FAB type M4 is apparent. Such cases may often be undocumented, because the deletions can be subtle. One patient with erythroleukemia shows an inversion of chromosome #11 involving band 11p15. Because the patients' fetal hemoglobin (HbF) became raised during the course of the disease, it is postulated that the hemoglobin beta chain gene at 11p15 may have been disrupted.

Adolescent↗