DNA rearrangement and restriction fragment length polymorphism within the first BCR intron in Philadelphia-positive acute leukemia

In some patients with Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemias, breakpoints on chromosome 22 are reported to occur within the first BCR intron. To analyze the breakpoints in chromosome 22 of Ph-positive acute leukemia patients without rearrangement of the 5.8 kb bcr, we cloned the 3' part of the first BCR intron using a synthetic DNA probe. During the course of study, we mapped the region of the deletion/insertion of 1 kb that causes a restriction fragment length polymorphism (RFLP) and found a racial difference in the frequencies of the alleles giving rise to this RFLP. Analyses of the patients' samples indicated that breakpoints were located within the 8.5 kb EcoRl fragment of the first BCR intron in two of five Ph-positive acute leukemia patients. The data, together with the previous reports, indicate that breakpoints within this approximately 50 kb intron are widely scattered, in contrast to those confined within the 5.8 kb bcr in chronic myelogenous leukemias.     

BCR rearrangement and cytogenetic findings in Philadelphia-positive chronic myelocytic leukemia in children

Eight children with Philadelphia (Ph1) chromosome positive chronic myelocytic leukemia (CML) were available for cytogenetic studies and breakpoint cluster region (bcr) rearrangement analysis as compared to the features of adults with Ph1-positive CML. In chronic phase additional abnormalities other than Ph1 chromosome were found in none of our cases. On the other hand, in blastic crisis all of 6 cases had additional chromosomal abnormalities like as i(17q), double Ph1 and +8. The frequency of the appearance of additional chromosomal abnormalities, especially i(17q), is higher in children than in adult cases. In the DNA of 7 of 7 examined patients, rearrangement of bcr could be demonstrated by Southern blot analysis. These findings were similar to those observed in adults. An analysis of the location of the bcr breakpoint indicated that 5' breakpoints were found in four cases who were long-term survivors, and two of the other cases had blastic crisis from the onset of the disease. These findings showed the cytogenetic findings of children with Ph1+CML were different from those of the adult cases in the frequency of the appearance of the additional chromosomal abnormalities, and the location of the bcr breakpoint in children cases might be different from that in the adult cases and influence its prognosis.     

Molecular analysis of chromosome 22 breakpoints in adult Philadelphia-positive acute lymphoblastic leukaemia

The Philadelphia (Ph) translocation, t(9:22)(q 34:q11), is found in the majority of patients with chronic myelogenous leukaemia (CML) as well as in approximately 20% of adult acute lymphoblastic leukaemia (ALL) patients. The chromosome 22 breakpoint in CML has been localized within a restricted 5.8 kb segment of DNA known as the breakpoint cluster region (bcr). To investigate the chromosome 22 breakpoint in ALL, we analysed five adult Ph-positive ALL patients for bcr rearrangement. Rearrangement was detected within bcr in two patients. However, in one patient the break occurred 5' to the first exon of bcr and in two patients the bcr region was not involved. We conclude that the identical cytogenetic marker, t(9:22), may yield a different genomic configuration in ALL and CML.     

成人Ph+急性淋巴细胞白血病不同BCR-ABL转录本特征及预后比较

目的 比较成人Ph+急性淋巴细胞白血病(ALL)不同融合基因转录本临床特征的差异,并探讨其与预后的关系.方法 回顾性分析1996年1月至2007年12月我院诊断为Ph+ALL患者(年龄≥15岁)的资料,比较两个BCR-ABL转录本组间的临床特征,探讨两组患者预后的差异.结果 (1)106例患者中位年龄34岁,中位白细胞数28.5×109/L.p190组67例,p210组35例,p210组较p190组中位年龄偏大(40岁、31岁,P=0.002),初诊血小板数高(49.5×109/L、31.5×109/L,P=0.012),中、重度脾大的发生率高(48.6%、25.4%,P=0.019).(2)两组患者完全缓解(CR)率分别为92.2%(59/64)和93.9%(31/33).(3)p190组中位总生存(OS)和中位无复发生存(RFS)分别为13个月和10个月;p210组中位OS和RFS分别为15个月和10个月.两组之间比较差异无统计学意义(P>0.05).结论 成人Ph+ALL中BCR-ABL以p190表达为主;p210患者较p190具有年龄偏大,初诊血小板数偏高,中、重度脾大发生率高的特点;两组在CR率、RFS和OS上无明显差异.     

Detection and localization of breakpoints within the first intron of the BCR gene in Ph1-positive leukemias

We studied breakpoints within the first intron of the BCR gene in 28 Philadelphia (Ph1)-positive acute leukemias (AL) and one Ph1-positive chronic myelogenous leukemia (CML), which lacked rearrangement of major breakpoint cluster region. With a series of genomic probes from this intronic region, we have detected chromosomal breaks in 19 of 28 patients with Ph1-positive AL and one patient with CML. Breakpoints were all located within 30 kb region at the 3' portion of the intron, same as in the previously reported cases. Breakpoints in our cases were not limited within "bcr-2" or "bcr-3", proposed by Chen, et al., but, occurred within or near Alu sequences. Our findings suggest that breakpoints are not randomly distributed throughout this intron, but, there may be some specific sequences that facilitate the process of chromosomal translocation.     

Ph1-positive, bcr-negative acute leukemias: clustering of breakpoints on chromosome 22 in the 3' end of the BCR gene first intron

About 50% of the Philadelphia-positive acute leukemias undergo molecular rearrangements outside the now classical bcr sequence (or M-BCR-1) rearranged in chronic myeloid leukemia (CML). Most of the breakpoints on chromosome 22 have been shown to be clustered in a 10.8-kb region of the first intron of the BCR gene (called bcr2 or m-BCR-1). In this report we examined two cases of Ph1 acute lymphoblastic leukemia in adult patients that exhibited breakpoints in a 5-kb segment of the BCR gene first intron, 16 kb upstream of the previously described cluster, suggesting the possibility of a second minor breakpoint cluster. In addition, the breakpoints on chromosome 9 were located in a region just 5' of the c-abl exon la.     

The first report of familial adult T-cell leukaemia lymphoma in the United Kingdom

We describe two siblings who developed adult T-cell leukaemia lymphoma (ATLL) within 4 years. Both were black of Afro-Caribbean extraction, but one had been born in the United Kingdom and had visited the Caribbean only once. Both patients were HTLV-1 seropositive, as was their mother; their father and brother were negative. The older sibling had the lymphoma form of ATLL, whilst the younger had chronic ATLL. The former was unresponsive to chemotherapy and died of progressive disease; the latter experienced transient responses to various treatments and is alive 5 years after presentation. Immunophenotyping showed a CD4⁺, CD25⁺ phenotype; Southern blot demonstrated a monoclonal integration of HTLV-I in the tissues involved. This report, of the first familial ATLL in the U.K., supports the suggestion of transmission of HTLV-I from mother to child and documents the development of ATLL in second-generation Caribbean immigrants.     

Possible involvement of protein kinase C activation in down-regulation of CD3 antigen on adult T cell leukaemia cells

Summary The role of protein kinase C (PKC) system on CD3 expression on adult T-cell leukaemia (ATL) was examined. The down-regulation of CD3 on ATL cells is reportedly induced by CD3 down-regulating factor (CD3DF) contained in serum and culture supernatants of leukaemia cells from acute type ATL patients. After we cultured normal PBMC with a PKC inhibitor, H-7, CD3DF activity for PBMC was reduced significantly. Culture with H-7 of HTLV-1 transformed T cells, ATL-2 cells whose CD3 expression had been decreased, led to enhancement of CD3 expression in a time-dependent manner. These findings suggest that CD3DF may play an important role as a PKC system activator, resulting in CD3 down-regulation.     

Relationship between chromosomal breakpoint and molecular rearrangement of T-cell antigen receptors in adult T-cell leukaemia.

The relationship between chromosome breakpoints associated with T-cell antigen receptor (TCR) genes and TCR-alpha/beta/tau/delta rearrangements of peripheral leukaemic cells in 8 Japanese patients with the acute type of adult T-cell leukaemia (ATL) was examined. Break of the 14q11 region with the assigned locus of TCR-alpha/delta was revealed in 6 patients, interstitial deletion of the 7q32-36 region with assigned locus of TCR-beta in 1 patient, and break of the 7p15 region with assigned locus of TCR-tau in 2 patients. Molecular analysis revealed TCR-alpha rearrangement in 7 patients, TCR-beta rearrangement in all patients, and TCR-tau rearrangement in 5 patients. TCR-delta was deleted in all patients. These findings indicate a close relationship between 14q11 anomaly and TCR-alpha rearrangement, which may play an important role in the leukaemogenesis of ATL.     

Oligoclonal proliferation of human T-cell leukaemia virus type 1 bearing T cells in adult T-cell leukaemia/lymphoma without deletion of the 3' provirus integration sites

We report a new case of an asymptomatic carrier with a deletion of a 3' HTLV-1 integration site. We further investigated whether these 3' deletions of flanking sequences may explain the oligoclonal pattern of HTLV-1 replication, evidenced by inverse PCR (IPCR) analysis of tumourous samples from patients with adult T-cell leukaemia (ATLL). 48 HTLV-1 3' integration sites, derived from tumourous DNA of five ATLL patients were sequenced. One dominant flanking sequence was obtained in the four samples harbouring a unique band after Southern-blotting. In one sample, which harboured two signals after Southern-blotting, IPCR amplification of diluted tumourous DNA revealed that these two sequences corresponded to one clone harbouring two integrated proviruses rather than to two distinct cellular clones, a result consistent with superinfection of the tumourous sample. In addition to integration sites corresponding to malignant clones, two to six oligoclonal forms were sequenced in four samples. No flanking sequence homology was found between clones derived from each patient, indicating that integration sites deletion in the vicinity of the provirus is a rare event in ATLL. The oligoclonal pattern of HTLV-1 replication in ATLL may result from clonal expansion of non-malignant HTLV-1-bearing clones within the sample and partly from HTLV-1 superinfection of monoclonal tumour cells.     

Additional chromosomal abnormalities and their prognostic significance in adult Philadelphia-positive acute lymphoblastic leukemia: with or without imatinib in chemotherapy

The study analyzed the characteristics and prognostic significance of additional chromosomal abnormalities in 110 Chinese adults with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL). Secondary aberrations were present in 60.9% of the cases. All chromosomes were involved in secondary aberrations, and chromosomes 9, 7, 21, 18, and 14 were most frequently abnormal. Fifty of 110 patients (45.5%) had at least one normal metaphase cell in their chromosome preparations at diagnosis. Patients with additional aberrations had shorter disease-free survival (DFS) and overall survival (OS) in chemotherapy combined with imatinib (ICT) group and only shorter DFS in conventional chemotherapy (CT) group. The existence of normal metaphase cells was associated with a superior survival in CT group, but not in ICT group. Patients with loss of chromosomes 7, 7p, 9, and 9p had inferior outcome compared to patients with other secondary aberrations and those without secondary aberrations, in both CT and ICT group.     

Histological and cytological heterogeneity of bone marrow in Philadelphia-positive chronic myelogenous leukaemia at diagnosis

Cytological and histological features of the bone marrow in Philadelphia-positive chronic myelogenous leukaemia (CML) at diagnosis were analysed in a prospective study. Formerly described (Frisch et al, 1984) subtypes GRAN and GRAN/MEG were found, and myelofibrosis and incipient blast crisis could also be detected. A more or less continuous spectrum of number and degree of atypias in megakaryocytes was found. Biopsy and imprint were complementary in making differential diagnosis of both subtypes. Cytologically, type GRAN/MEG was characterized by a mixed proliferation of neutrophil, eosinophil and basophil series, besides proliferation of megakaryocytes. Type GRAN showed a predominantly neutrophilic proliferation. The importance of performing bone marrow analysis in evaluation of CML patients is discussed.     

Relationship of serum lactate dehydrogenase level with first remission length in adult acute lymphocytic leukaemia

Several features have a prognostic value in adults with acute lymphocytic leukaemia (ALL). However, in about two-thirds of all cases prognosis remains quite variable, with a substantial number of early relapses. This study shows in 118 adult patients who attained complete remission (CR) between 1978 and 1984 that pretreatment serum total lactate dehydrogenase (LDH) activity was inversely correlated with first CR length. The prognostic value of LDH was higher than that of any other features both in univariable and in multivariable analysis. The value was significant in the whole series as well as in patients who lacked other high risk features. Among non-high risk and low-WBC count cases, patients with LDH less than or equal to 500 U/l had a median first CR duration of 27 months, and a projected 5-year relapse free survival of 36%, versus 9 months and 12% of patients with LDH greater than 500 U/l. These results fit well with the results of a study of ALL in children, and suggest that pretreatment serum total LDH activity is an important risk determinant in adult ALL.     

Validation of the European Prognostic Index for younger adult patients with acute myeloid leukaemia in first relapse

In order to validate the European Prognostic Index (EPI) for patients 相似文献   

A polymorphism in exon b2 of the major breakpoint cluster region (M-bcr) identified in chronic myeloid leukaemia patients

The BCR/ABL junctional region and the b3 exon from chronic myeloid leukaemia (CML) patients were sequenced. In all 21 samples analysed the junctional region, as well as the b3 exon of 8 b3a2 mRNA molecules, presented no differences to the already described sequences. However, we identified a polymorphic base in the b2 exon in two out of seven b3a2 samples, four out of 10 b2a2 samples and all four b3a2/b2a2 samples analysed. In the eighth position before the junctional region of BCR/ABL cDNA, a cytosine replaces thymine in these cases. The polymorphism described here could be a useful marker for the differentiation of normal and rearranged BCR alleles in heterozygotes.     

Acute hepatitis due to Mycoplasma pneumoniae infection without lung involvement in adult patients

Mycoplasma pneumoniae has been associated with cholestatic hepatitis in children, while in adults, the lack of liver involvement has been considered as a typical feature of M. pneumoniae infection. Controversial data have been reported about the possibility of liver involvement with M. pneumoniae community-acquired pneumonia. We present two cases of acute hepatitis associated with M. pneumoniae infection without lung involvement.