ISSN:1042-8194    

DOI:10.3109/10428199309047854

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

ISSN:1042-8194    

DOI:10.3109/10428199309047855

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The Philadelphia chromosome (Ph), i.e., the reciprocal translocation t(9;22)(q34;q11), is found with great specificity in bone marrow cells from patients with chronic myeloid leukemia (CML). Variant Ph-producing translocations, seen in 5–10% of all patients, are all complex and involve the same molecular rearrangement as the regular t(9;22). Patients with classic and variant Ph-producing translocations are clinically and hematologically identical, and as a group differ from Ph-negative CML patients. In all patient groups, the occurrence of additional chromosome changes is an ominous sign indicating that disease progression is imminent. The chromosome changes occurring in excess of the Ph in CML are clearly nonrandom and two pathways of cytogenetic evolution may be distinguished. Major route changes comprise trisomy 8, i(17q), trisomy 19, and an extra Ph; totally, 71% of Ph-positive CML patients have at least one of these four major route changes. Six minor route changes, including five numerical abnormalities (-7, -17, +17, +21, and -Y) but also one structural aberration, t(3;21) (q26;q22), have been identified. At least one of these changes is found in 15% of all Ph-positive CML cases. Altogether, the four major route aberrations and the six minor route changes are present as part of the clonal evolution in 86% of CML with cytogenetic abnormalities in addition to the Ph chromosome.

ISSN:1042-8194    

DOI:10.3109/10428199309047856

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The presence of the BCR/ABL chimeric gene is the hallmark of defined types of human leukemia. To increase our knowledge of the oncogenic processes and to develop a model for this type of leukemia we generated a BCR/ABL (P190) transgenic mouse line. Over 95% of mice of this line die of leukemia or leukemia/lymphoma within 35–200 days of age. Karyotypically visible genetic alterations were absent from the early stages of BCR/ABL generated leukemia. A high frequency of aneuploidy was found in advanced leukemia indicating a primary and pivotal role for BCR/ABL in leukemogenesis. Moreover, the data suggest that BCR/ABL has a destabilizing effect on the regulation of the cell cycle. BCR/ABL expression was also found in tissues other than hematopoietic cells. However, this did not result in the development of solid tumors, strongly suggesting that the oncogenicity of BCR/ABL is limited to the hematopoietic lineage.

ISSN:1042-8194    

DOI:10.3109/10428199309047857

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Parts of the Bcr/Abl hybrid transcript supposed to be important for its transforming ability were sequenced in a series of CML blast crises, in order to evaluate the possible presence of alterations responsible for the disease transition from the chronic to the acute phase. In addition, the N and Ki-ras as well as the p53 involvement was investigated by exploring their structure and expression in the same patients. We used traditional types of molecular analysis including Southern and Northern blot, together with methods that allow a rapid detection of point mutations and microdeletions, such as SSCP, single strand conformation polymorphism and direct sequencing. The results obtained may be summarized as follows: no alterations were found in the parts of the Bcr/Abl transcripts investigated in the present study (SH2, SH3 and the region surrounding codon 832); p53 alterations were observed in 5% and N-and Ki-RAS mutations in 5% of the cases examined. These molecular defects are therefore responsible for the clinical progression of the Ph1-positive CML only in a minority of cases.

ISSN:1042-8194    

DOI:10.3109/10428199309047858

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

In chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) the Ph1chromosome (22q”) is the most frequent chromosomal aberration encountered. At the molecular level thec-ablgene from chr. 9 is translocated to thebcrgene on chr. 22. As a result, a chimericbcr-ablgene is generated, which encodes chimeric proteins. Since these proteins are only expressed in Ph1positive cells, they are per definition tumor-specific.In this report we describe the reactivity of polyvalent antisera raised against synthetic peptides corresponding to the tumor-specificbcr-abljunctions. Native chimeric proteins were specifically recognized by these junction-specific antisera. Therefore we conclude that thebcr-abljunctions are antigenically exposed on the chimeric proteins. We discuss the relevance of these antisera for CML and ALL diagnosis.

ISSN:1042-8194    

DOI:10.3109/10428199309047859

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The Detection of Residual Minimal Disease (RMD) in CML after Therapy: Kathryn E. Fuscaldo and Isadore Brodsky, Hahnemann University, Philadelphia, Pa. USA.Chromosomal and Southern Blot analyses have been used to diagnose Leukemias characterized by non-random chromosomal rearrangements. They have also been used to monitor disease progression during and after chemotherapy. These methodologies are often not adequate to detect RMD after ablative therapy and Bone Marrow Transplantation (BMT). Molecular quantitative Polymerase Chain Reaction (PCR) techniques have been developed to detect low levels of leukemic cells in patients with diseases characterised by fusion transcripts. 95% of Chronic Myelocytic (CML) and 15–25% of Acute Lymphoblastic Leukemia (ALL) patients are Ph1 producing a fusion transcript between theablproto-oncogene9and thebcrgene.22Acute Promyelocytic Leukemia (APL) with break points in the (RAR) gene15and thezylgene17also produces a fusion transcript. The significance of PCR for 1) detecting RMD after therapy, 2) correlating low levels of leukemic cells over time with therapeutic response and long term remission and 3) assessing the effect of RMD during remission by sequential analyses is discussed.

ISSN:1042-8194    

DOI:10.3109/10428199309047860

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

We describe the methodology and application of the polymerase chain reaction to detect BCR-ABL mRNA as a marker for CML cells. The technique is highly sensitive enabling the routine detection of 1 leukaemic cell in 105or 106normal cells and is therefore the most sensitive method available for detecting minimal residual disease. Analysis of marrow or blood from 80 patients after bone marrow transplantation for CML shows that residual leukaemia is often detectable for several months but that most subsequently become PCR negative. Patients who relapsed were all PCR positive before the detection of Philadelphia positive metaphases in bone marrow aspirates.

ISSN:1042-8194    

DOI:10.3109/10428199309047861

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The BCR-ABL gene plays a central role in the pathogenesis of chronic myelogenous leukemia. Despite a detailed understanding of the regions of BCR and ABL required for transformation by BCR-ABL, little is known about the signalling pathway by which BCR-ABL causes transformation. The nuclear oncogene c-myc plays a critical role in BCR-ABL transformation. Levels of c-myc RNA are high in cells transformed by BCR-ABL, and overexpression of dominant negative forms of myc blocks transformation by BCR-ABL. These findings suggest that myc may be a useful therapeutic target in BCR-ABL-related leukemias.

ISSN:1042-8194    

DOI:10.3109/10428199309047862

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of the myeloid lineage. It has a progressive course typified by the transition from the chronic phase to the accelerated phase and on to blast crisis. The hallmark of CML is the translocation between chromosomes 9 and 22 that results in the chimericBCR-ABLgene encoding p210BCR-ABL. The oncogenic potential of this protein has been validated, and it is believed that it contributes in a critical way to the initiation of CML. However, the secondary genetic forces responsible for the transition from the chronic state to the fully blastic stage are not clear. Evidence for chromosomal instability includes the clonal evolution which characterizes advanced CML. In regard to specific genetic aberrations, sporadic reports have shown alterations in H-RAS, c-MYC, retinoblastoma, and P53 genes, as well as production of p190BCR-ABLduring the progression of CML. In addition, we have recently found evidence for excessive interleukin-1βproduction, acting in an autocrine and/or paracrine manner, in the more advanced stages of the disease. Taken together, current data suggest that multiple molecular pathways lead to disease progression, and that distinct subsets of genetic alterations exist in blast crisis patients.

ISSN:1042-8194    

DOI:10.3109/10428199309047863

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor