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PubMedDate not supplied

M-BCR breakpoint location does not predict survival in Philadelphia chromosome-positive chronic myeloid leukemia.

BACKGROUND: Some reports in the recent literature have shown that the site of molecular rearrangement within the M-BCR area may have a prognostic value in Ph1 + CML patients. A number of studies have, however, failed to demonstrate this finding. Here we report the molecular rearrangements of 107 patients and their clinical follow-up. METHODS: Localization of the breakpoints was determined according to conventional criteria, after digestion with 2 to 4 restriction endonucleases and hybridization with 1 or 2 molecular probes. RESULTS: Sixty two patients were rearranged in the 5' area and 45 in the 3' area: there was no difference between the survival curves of the two groups, at least not after 3 years of follow-up. CONCLUSIONS: The site of the breakpoint within the M-BCR has no prognostic significance in our series.

Adult↗
PubMedDate not supplied

Molecular diagnosis of Philadelphia chromosome-positive chronic myeloid leukemia.

BACKGROUND: In virtually all Ph1 chromosome-positive CML patients, the breakpoint on chromosome 22 maps in a very restricted area of 5.8 Kb, which has been named "breakpoint cluster region" or "bcr". Several molecular probes of this region are presently available, and this makes the molecular diagnosis of CML a useful approach which can be particularly important in those cases in which cytogenetic analysis does not reveal the presence of a Ph1 chromosome. Here we report the problems and our experience during the molecular analysis of the 478 patients examined so far. METHODS: Molecular analyses were performed after digestion of the DNA with 2 to 4 restriction enzymes and hybridization with different probes. Individual samples were subjected to PCR since no rearrangements had been obtained with Southern blotting. RESULTS: Rearrangement bands were detected in all the samples examined. In 473 cases the breakpoint was located within the bcr. In one of these cases, it was detected only after PCR analysis, and in two cases only after the use of the PHL/BCR probe. In 5 cases the breakpoint was localized either 5' or 3' with respect to the bcr. CONCLUSIONS: In this paper, the criteria for a correct molecular diagnosis of CML are presented. The "PHL/BCR" probe appeared to be very specific and time-saving, since it required only one digestion to evidence the rearrangement. Our results confirm the high specificity of the breakpoint on chromosome 22 in CML and the relatively rare incidence of molecular variants.

Base Sequence↗
PubMed1992

Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia.

Although rare cells expressing the bcr/abl fusion transcript can be detected by the polymerase chain reaction (PCR) in patient blood or marrow after allogeneic bone marrow transplant (BMT) for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukemia (CML), the prognostic significance of this finding is unknown. This paper reports clinical, cytogenetic, and molecular data derived from 64 CML patients following allogeneic BMT. Nested primer PCR was performed on patient blood and bone marrow samples to detect the presence of residual bcr/abl (+) cells in CML patients considered to be in clinical remission at the time of study. Bcr/abl transcripts were detected in 37 of 64 patients for at least one timepoint post-BMT. Thirteen of these 37 bcr/abl (+) patients have subsequently relapsed, as defined by clinical and/or persistent cytogenetic findings, in contrast to 0 relapses among the 27 bcr/abl (-) patients (P = .0025). The median time from first (+) bcr/abl PCR signal to relapse was 150 days (range 90 to 832). Fifty-four patients were studied at two or more timepoints post-BMT: five of eight patients persistently bcr/abl (+) have relapsed; 5 of 23 patients with both bcr/abl (+) and (-) assays during follow-up have relapsed; and none of 23 patients persistently (-) have relapsed (cumulative actuarial relapse rates 77%, 20%, and 0%, respectively, P = .0017). These data indicate that among CML patients in apparent clinical remission after BMT, nested primer bcr/abl PCR can define subgroups with low, intermediate, and high risk of relapse. The pattern of bcr/abl PCR detection after transplant may aid in the development of trials designed to reduce the risk of relapse, or allow for early intervention in patients who fail to clear the malignant clone.

Base Sequence↗
PubMed1991

Appearance of acute leukemia-associated P190BCR-ABL in chronic myelogenous leukemia may correlate with disease progression.

The Philadelphia translocation in chronic myelogenous leukemia (CML) results in the production of a 210 kD BCR-ABL protein. In contrast, in 50% of Philadelphia-positive acute leukemias, the translocation results in the production of a 190 kD BCR-ABL protein. To investigate the hypothesis that the production of P190 may be associated with the progression from chronic phase to blast crisis in CML, we used polymerase chain reaction to analyze blood from 37 patients with accelerated phase/blast crisis CML for the transcripts coding for the P210BCR-ABL and P190BCR-ABL. The mRNA encoding for P210 was detected in all patients. In three patients, mRNA encoding both P210 and P190 was present. In two of these three patients, samples were available from the time of initial diagnosis. Analysis of these samples did not reveal any transcripts for P190. We conclude that in some patients the appearance of P190BCR-ABL may correlate with transformation to a more aggressive, terminal phase of CML.

Adolescent↗
PubMed1990

Expression of bcr-abl fusion transcripts following bone marrow transplantation for Philadelphia chromosome-positive leukemia.

A modified polymerase chain reaction (PCR) procedure was used to study the expression of bcr-abl fusion transcripts following allogeneic bone marrow transplantation (BMT) for Philadelphia chromosome (Ph1) positive acute and chronic leukemias. The technique was applied to RNA preparations of peripheral blood and bone marrow cells from 10 patients with chronic myelogenous leukemia (CML) and one patient with acute lymphoblastic leukemia (ALL), all of whom had undergone allogenic BMT and were in clinical and cytogenetic remission. Pre-BMT samples available for eight of 11 patients contained detectable bcr-abl fusion products serving as a baseline for comparison to post-BMT studies. Six patients showed no PCR-detectable bcr-abl transcripts in each of several serial analyses post-BMT (1-36 months post-BMT). The remaining five patients demonstrated various patterns of bcr-abl transcript expression after transplantation. In three patients, bcr-abl transcripts persisted for up to 3 months post-BMT but subsequently were undetectable. Molecular relapse was observed 3 and 6 months post-BMT in the remaining two patients whose earlier post-BMT samples showed no bcr-abl fusion transcripts. No bcr-abl transcripts were detected in subsequent samples from both of these patients 6 months and 1 year post-BMT, respectively. These data confirm that Ph1 carrying cells expressing the bcr-abl fusion mRNA may persist or recur for several months following BMT in the absence of clinical and cytogenetic relapse. The significance of these observations is discussed with respect to results reported recently by others using similar techniques.

Bone Marrow Transplantation↗
PubMed1988

Absence of alternative splicing in bcr-abl mRNA in chronic myeloid leukemia cell lines.

The major consequence of the Philadelphia (Ph) translocation in chronic myeloid leukemia (CML) is the formation of a bcr-abl hybrid oncogene encoding a tumor cell-specific protein P210bcr-abl. In contrast to this, in Ph chromosome-positive acute lymphoblastic leukemia (Ph + ALL), a P190bcr-abl can be observed. This P190bcr-abl has been implicated in acute rather than chronic leukemogenesis. Therefore, it can be hypothesized that the transition from chronic to blast phase in CML is accompanied by an alternative splice in the bcr-abl mRNA, which results in a switch of the production of P210bcr-abl into P190bcr-abl. Initial S1 nuclease protection mapping supported this theory. However, this result appears to be based on an artifact in the S1 analysis. By using the polymerase chain reaction we provide evidence for the absence of alternative splicing in bcr-abl mRNA in two CML blast crisis cell lines.

Blast Crisis↗
PubMed1988

Detection of the molecular abnormality in chronic myeloid leukemia by use of the polymerase chain reaction.

The bcr-abl translocation characteristic of chronic myeloid leukemia (CML) was detected by the polymerase chain reaction (PCR) modified to use mRNA as the starting material. Amplification of a sequence spanning the bcr-abl junction was obtained by using peripheral blood cells from all of 20 patients with classic CML, one patient with acute lymphoblastic leukemia probably secondary to CML, and two cell lines derived from patients with CML. The presence of bcr exon 3 in the mRNA was determined from the size of the amplified sequence; it was present in 14 and absent in seven patients. One leukemic cell per 1,000 nonleukemic cells could be readily detected, thus indicating the great sensitivity of the method. This technique is of routine value in CML both for diagnosis and for following the course of treatment.

Blast Crisis↗
PubMed1983

Single-gene abrogation of spontaneous pleomorphic SJL/J mouse reticulum cell sarcoma expression.

Inbred SJL/J and A.SW/SnJ mice have been bred to produce (SJL female X A.SW male)F1 and A.SW female X SJL male)F1 mice. F1 mice were then crossed to produce (SJL female X A.SW male)F2 and (A.SW female X SJL male)F2 mice. The inbred, F1, and F2 populations were followed for 2 years to determine the incidences of spontaneous reticulum and sarcoma (RCS) expression. SJL mice had a greater than 90% incidence of RCS, although F1 mice showed almost no RCS. The incidence of RCS in the F2 populations was 24.1%. These data were consistent with the hypothesis that in F1 and F2 populations a single dominant A.SW gene is able to suppress the expression of the pleomorphic RCS disease characteristic of the SJL mouse. This gene was not an H-2 gene, since the two strains were congenic with respect to the major histocompatibility complex; this gene was not on the Y-chromosome, and its phenotypic expression was not inherited in an X-linked manner.

Animals↗
PubMed1994

[Detection of bcr-abl transcripts in "minimal residual disease" in chronic myelogenous leukemia by nested polymerase chain reaction (PCR)].

We compared two non-radioactive PCR methods, a single step PCR and a nested PCR, for detecting bcr-abl transcripts in patients with chronic myelogenous leukemia (CML). The nested PCR assay was about thousand times more sensitive than the single step PCR. In 75 clinical samples tested in parallel, the sensitivity for the single step PCR and the nested PCR was 43.2% and 91.9%, respectively. In all 17 samples of 9 patients before bone marrow transplantation (BMT), bcr-abl transcripts were detected by the single step PCR. After BMT, 5 (9.8%) of 51 samples of 4 patients were positive by the single step PCR and 17 (33.3%) of 7 patients by the nested PCR. These data indicate that single step PCR may miss minimal residual disease whereas nested PCR is a sensitive alternative to the use of radioactive probes.

Bone Marrow Transplantation↗
PubMed1994

Persistence of myeloid progenitor cells expressing BCR-ABL mRNA after allogeneic bone marrow transplantation for chronic myelogenous leukemia.

Previous studies have shown that tumor-specific bcr-abl mRNA can often be detected by polymerase chain reaction. (PCR) for months to years after allogeneic bone marrow transplantation (BMT) for chronic myelocytic leukemia (CML). Nevertheless, the presence of bcr-abl mRNA by itself does not invariably predict for clinical relapse post-BMT. This has led to the hypothesis that bcr-abl mRNA might be expressed in cells that have lost either proliferative or myeloid differentiation potential. To directly characterize the cells detected by PCR in patients with CML after allogeneic BMT, we first identified five individuals in whom PCR-positive cells could be detected at multiple times post-BMT. Bone marrow samples from these individuals were cultured in vitro and single erythroid, granulocytic, and macrophage colonies, each containing 50 to 100 cells, were examined for the presence of bcr-abl mRNA by PCR. PCR-positive myeloid colonies could be detected in four of five individuals in marrow samples obtained 5 to 56 months post-BMT. Overall, 7 of 135 progenitor cell colonies (5.2%) were found to be PCR-positive. The expression of bcr-abl mRNA appeared to be equally distributed among committed erythroid, macrophage, and granulocyte progenitors. These patients have now been followed-up for an additional 20 to 33 months from the time of progenitor cell PCR analysis but only one of these individuals has been found to have cytogenetic evidence of recurrent Ph+ cells. These results show that long-term persistence of PCR-detectable bcr-abl mRNA after allogeneic BMT can be caused by the persistence of CML-derived clonogenic myeloid precursors that have survived the BMT preparative regimen. These cells continue to have both proliferative and myeloid differentiation capacity in vitro. Nevertheless, these PCR-positive cells do not appear to either expand or differentiate in vivo for prolonged periods, suggesting the presence of mechanisms for suppression of residual clonogenic leukemia cells in vivo.

Adult↗
PubMed1994

Granulocyte colony-stimulating factor receptor mRNA upregulation is an immediate early marker of myeloid differentiation and exhibits dysfunctional regulation in leukemic cells.

The identification of early markers of myeloid differentiation can facilitate an understanding of how differentiation is arrested in leukemogenesis. Using murine bone marrow and the granulocyte-precusor cell line 32Dc13, we show that message for the granulocyte colony-stimulating factor receptor (G-CSFR) is upregulated by G-CSF in an immediate early fashion that is specific to the differentiation pathway and is antagonized by interleukin-3. We further show that G-CSFR message is superinduced by cycloheximide and that these patterns of regulation are altered in leukemic cell lines. In particular, the v-abl oncogene product supresses both ligand-mediated upregulation and superinduction of the G-CSFR gene.

Animals↗
PubMed1993

Nucleotide sequence of the hemG gene involved in the protoporphyrinogen oxidase activity of Escherichia coli K12.

The hemG gene of Escherichia coli K12 is involved in the activity of protoporphyrinogen oxidase, the enzyme responsible for the conversion of protoporphyrinogen IX into protoporphyrin IX during heme and chlorophyll biosynthesis. The gene is located at min 87 on the genetic map of E. coli K12. The hemG gene was isolated by a mini-Mu in vivo cloning procedure. As expected, the hemG gene is able to restore normal growth to the hemG mutant, and the transformed cells display strong protoporphyrinogen oxidase activity. Sequencing of the hemG gene allowed us to identify an open reading frame of 546 nucleotides (181 amino acids), within the minimal fragment able to complement the mutant. The presumed molecular mass of the HemG protein is 21,202 Da, in agreement with values found by SDS-PAGE, in a DNA-directed coupled transcription-translation system. The identity of the first 18 amino acids at the amino-terminal end of the protein was confirmed by microsequencing. To our knowledge, this is the first cloning of a gene involved in the protoporphyrinogen oxidase activity of E. coli.

Amino Acid Sequence↗
PubMed2002

The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.

Chronic myeloid leukaemia (CML) is characterized by the presence of the BCR-ABL fusion gene, usually in association with the t(9;22)(q34;q11) translocation. We report here the identification and cloning of a rare variant translocation, t(4;22)(q12;q11), in two patients with a CML-like myeloproliferative disease (MPD). RT-PCR indicated that both patients were negative for BCR-ABL, but FISH analysis suggested that the BCR gene was rearranged. Since other translocations in MPDs frequently involve tyrosine kinases, we designed a multiplex PCR to search for mRNA fusions between BCR and three potential partner genes at 4q12: KIT, KDR and PDGFRA. An unusual inframe BCR-PDGFRA fusion mRNA was identified in both patients, with either BCR exon 7 or exon 12 fused to short BCR intron-derived sequences, which were in turn fused to part of PDGFRA exon 12. Sequencing of the genomic breakpoint junctions showed that the chromosome 22 breakpoints fell in BCR introns whereas the chromosome 4 breakpoints were within PDGFRA exon 12. This is the first report of a fusion gene that involves PDGFRA. Our findings indicate that apparently simple cytogenetic variants of t(9;22) do not always mask a cryptic BCR-ABL fusion, even when found in association with clinical and haematological indications of CML.

Adult↗
PubMed1993

Possible role of activated ras genes in human esophageal carcinogenesis.

Activation by point mutation of the H-, K- and N-ras genes is found in many tumors. However, no such mutation has yet been found in human esophageal carcinomas from various parts of the world. We have confirmed the absence of mutation at codons 12, 13 and 61 of K- and N-ras and at codons 12 and 61 of H-ras in 25 primary tumors obtained in France. In contrast, among 7 human esophageal carcinoma cell lines (TE1, TE2, TE3, TE8, TE9, TE10, TE13) with different degrees of tumorigenicity in nude mice, 3 highly tumorigenic lines (TE1, TE2 and TE8) exhibited activation of ras oncogenes; 2 showed a G35 to A35 transition of K-ras gene and one a H-ras G35 to T35 transversion. Since these cell lines had been established from tumors of Japanese patients from Sendai, we examined 3 primary esophageal tumors from Tokyo and 19 from Sendai, including the primary tumors from which the TE cell lines had been derived. No ras mutation was detected, which suggests that the ras gene mutations in the TE cell lines are either due to their long-term culture or that only a small portion of the original tumors contained such mutations. In order to directly examine the effect of ras gene mutation, one of the non-tumorigenic cell lines, TE13, was transfected with a plasmid coding for a mutated H-ras gene (G35 to T35). Transfected clones expressing high levels of mutated ras gene were able to induce tumors in nude mice. Thus, although no primary human esophageal tumor contained mutated ras genes, our studies do not exclude a significant role of mutated ras genes in cell proliferation and malignant transformation of human esophageal cells.

Adult↗