Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty six patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) treated with IFN-alpha were classified on the basis of the fusion pattern of BCR/ABL chimeric mRNA determined by a reverse-transcriptase-polymerase chain reaction (RT-PCR) method. The relationship between the fusion pattern of BCR/ABL mRNA and the clinical outcome was also analysed. Twelve patients showed M-bcr exon 3/ABL exon 2 (B3/A2) chimeric mRNA and nine had M-bcr exon 2/ABL exon 2 (B2/A2) mRNA. Eleven of the 12 patients with B3/A2 achieved complete hematological response with IFN-alpha therapy, as did three of the nine patients with B2/A2. The mean duration to blastic crisis was significantly longer in the B3/A2 patients (mean 52.4 months) than in the B2/A2 patients (mean 26.2 months) (p less than 0.01). These results suggest that the fusion pattern of BCR/ABL mRNA may affect the therapeutic response to IFN-alpha and clinical outcome in CML patients.
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PMID:Possible correlation between fusion pattern of BCR/ABL mRNA and clinical response to alpha-interferon in chronic myelogenous leukemia. 151 6

Eight cases of Philadelphia positive acute leukemia (Ph+AL) were compared with 13 cases of Ph+ chronic myelogenous leukemia in blast crisis (BC) and 10 cases of Ph negative acute lymphoblastic leukemia (Ph-ALL) based on the clinical and molecular biological findings. Distinguishing clinical features were a high leukocyte count (median; 147.9 x 10(3)/microliters) for Ph+AL, and a high incidence of tumor formation and basophilia for BC. A cytogenetic study demonstrated the disappearance or marked reduction of Ph+ metaphases in Ph+AL in remission, while Ph+ cells persisted in BC. The major bcr gene was not rearranged in 4 Ph+AL cases, whereas it was found rearranged in 4 other cases of Ph+ AL and 6 cases of BC. Reverse transcriptase polymerase chain reaction technique demonstrated the presence of minor bcr/abl mRNA in the former three cases, and major bcr/abl mRNA in the latter 4 cases. Remission rates were 63% for Ph+AL, 38% for BC, and 100% for Ph-ALL, and the 50% survival were 12, 5 and 29 months, respectively. It was concluded that Ph+AL can be differentiated from BC by a marked reduction of Ph+ cells at remission, and that the prognosis of Ph+AL is better than BC, but worse than Ph-ALL.
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PMID:[Clinical and molecular biological study of Ph positive acute leukemia: comparison with blast crisis of chronic myelogenous leukemia and Ph negative acute lymphoblastic leukemia]. 163 16

Philadelphia-chromosome positive chronic myeloid leukemia cells in chronic phase (CML-CP) or blast crisis (CML-BC) and normal bone marrow cells (NBMC) were incubated in vitro with antisense oligonucleotide specific against the BCR/ABL breakpoint junction to examine the possibility of selective inhibition of leukemia growth. Growth capability was determined in vitro by colony assay in semisolid medium in the presence of interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF). The 18-mer antisense directed against the specific BCR/ABL mRNA breakpoint region diminished the colony formation by CML-CP and CML-BC cells, but not by NBMC. Scrambled oligomer did not affect significantly the growth of leukemic and normal cells. If CML-BC cells were mixed with NMBC and incubated with specific BCR/ABL antisense oligomer, leukemic colonies were selectively inhibited, as was shown by reverse, transcriptase-polymerase chain reaction (RT-PCR) performed to detect BCR/ABL mRNA in single colonies. These results confirm the possibility of selective inhibition of leukemia cells by antisense treatment.
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PMID:Gene-targeted specific inhibition of chronic myeloid leukemia cell growth by BCR-ABL antisense oligodeoxynucleotides. 179 39

Thirty-five patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) were classified on the basis of the fusion pattern of bcr-abl mRNA determined by the reverse-transcriptase-polymerase chain reaction (RT-PCR) method. Semiquantitative assay of the bcr exon 2/abl exon 2 fused mRNA (b2-a2) and bcr exon 3/abl exon 2 fused mRNA (b3-a2) resulted in 21 patients showing b3-a2 type mRNA, seven showing b2-a2 type and seven showing coexpression. Quantification of the autoradiographic signals of amplified products was estimated using an MCID image analysis system. The relative intensity was defined as the ratio of bcr-abl signal to that of beta-actin. The relationship between the semiquantified bcr-abl mRNA and the platelet/megakaryocyte counts was analyzed. A possible correlation was found between the semiquantified b3-a2 type mRNA and the platelet (p < .05, N = 28) and megakaryocyte (p < .05, N = 13) counts of these patients. This finding suggests the possibility that b3-a2 mRNA may affect the thrombopoietic activity in Ph1-positive CML in a dose-response manner.
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PMID:Possible correlation of b3-a2-type bcr-abl messenger RNA defined by semiquantitative RT-PCR to platelet and megakaryocyte counts in Philadelphia-positive chronic myelogenous leukemia. 752 Jul 86

The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine relative levels of WT1 gene expression (defined in K562 cells as 1.00) in 45 patients with acute myelogenous leukemia (AML), 22 with acute lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AMLL), 23 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma. Significant levels of WT1 gene were expressed in all leukemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia, the levels of WT1 gene expression for NHL were significantly lower or even undetectable. Clear correlation was observed between the relative levels of WT1 gene expression (< 0.6 v > or = 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), disease-free survival, and overall survival than those with > or = 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 gene expression. The quantitation of the WT1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Continuous monitoring of the WT1 mRNA was performed for 9 patients with acute leukemia. In 4 patients, MRD was detected 2 to 8 months before clinical relapse became apparent. In 2 other patients, the WT1 mRNA gradually increased after discontinuation of chemotherapy. No MRD was detected in the remaining 3 patients with AML who received intensive induction and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PML/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detected MRD comparable with that obtained from quantitation of WT1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic leukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia.
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PMID:WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. 794 79

This report describes a patient presenting with acute myeloid leukaemia (AML-FAB classification M2). Phenotypic markers were positive for cells of the myeloid lineage, but negative for monocyte/macrophage, megakaryocyte, and T-cell lineages. The occasional blast was positive for CALLA. All blasts carried the Philadelphia chromosome (Ph+), with 20% also harbouring a monosomy 7 (a cytogenetic marker for AML). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed the presence of two BCR/Abl mRNA transcripts; b2a2, the CML-type and E1a2, the ALL-type. Immunoglobulin (Ig) gene analysis demonstrated the presence of a small population of cells containing rearranged Ig genes. After a short remission, the patient relapsed. At relapse the leukaemia had undergone a major phenotypic switch from AML to ALL, with blasts bearing B-cell markers. Ig gene analysis confirmed a monoclonal population of B-cells. The Ph+ persisted, but the monosomy 7 had disappeared. The same two BCR/Abl mRNA transcripts were found at relapse as at presentation. To our knowledge, this is the first report of an AML simultaneously expressing BCR/Abl transcripts from both the minor and major BCR. The possible mechanisms of this dual expression are discussed.
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PMID:A Ph+ acute myeloid leukaemia expressing both CML-type and ALL-type BCR/ABL mRNA transcripts. 795 Sep 25

The translocation t(15;17)(q22;q21) is seen exclusively in patients with acute promyelocytic leukemia (APL) and in the promyelocytic blast crisis of chronic myeloid leukemia (CML). This translocation juxta-poses the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor-alpha (RARA) gene on chromosome 17, resulting in the formation of a chimeric mRNA transcript. We describe a patient with the microgranular variant form of APL, with no detectable cytogenetic abnormality of either chromosomes 15 or 17, who nevertheless had juxtaposition of PML and RARA genes and expressed a chimeric transcript. Conventional cytogenetics showed the karyotype 46,XY,d-er(3)t(3;8)(p25;q12). Fluorescent in situ hybridization (FISH) with paints for chromosomes 8, 15, and 17 confirmed the presence of structurally intact chromosomes 15 and 17 and trisomy for chromosome 8q. Nevertheless, FISH using cosmid probes for PML and RARA showed their juxtaposition on one chromosome 15 homolog. Both genes were also present on their normal homologs; in addition, part of the RARA gene was still present on the remaining chromosome 17. DNA analysis by Southern blotting, performed with a variety of probes including PML, RARA and retinoic acid receptor-beta (RARB), showed a rearrangement in PML. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the existence of hybrid transcripts of 276, 455 bp and 623 bp, from PML-RARA on the der(15) chromosome, consistent with alternate exon splicing of the long form of the transcript occurring in 50% to 60% of patients with APL. Our results show that APL patients with cytogenetically normal chromosomes 15 and 17 may, nevertheless, have involvement of both PML and RARA genes defining a subgroup of APL, t(15;17)-negative/PML-RARA-positive which is analogous to Philadelphia chromosome-negative/BCR-ABL-positive CML. In this case, the presence of chimeric transcripts suggests that treatment with all-trans RA may be warranted in APL, even in the absence of detectable cytogenetic change, showing the usefulness of RT-PCR or FISH to aid diagnosis.
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PMID:Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17. 818 Mar 90

Despite the marked expansion of leukemic cells observed in the hematopoietic system of chronic myeloid leukemia (CML) patients, there is clinical and experimental evidence that normal nonclonal cells persist in the bone marrow (BM) and peripheral blood (PB) of patients in the early chronic phase. In this study, we attempt to select the benign progenitor-enriched population from the PB of CML patients. The CD34+ cells isolated from the PB of 12 CML patients in the chronic phase were treated with low doses (5 or 10 micrograms/mL) of 5-fluorouracil (5-FU). We expanded these cells for 7 days in liquid cytokine-mediated cultures. This expansion in the presence of interleukin-1 (IL-1) plus stem cell factor (SCF) plus IL-3 or leukemia inhibitory factor (LIF) plus SCF plus IL-3 seemed at least to preserve the initial clonogenic potential of CD34+ and 5-FU-resistant CD34+ cells. For the presence of BCR-ABL, mRNA from each of the 12 patients was studied by reverse-transcriptase-polymerase chain reaction (RT-PCR) on 10-15 pooled CFU-GM colonies plucked from methylcellulose cultures of starting and expanded populations. Although all PCR results were positive for colonies harvested before liquid culture, we were able to identify BCR-ABL-negative colonies from an expanded CD34+ population cultured in the presence of recombinant cytokines in 11 of 12 patients studied. 5-FU pretreatment of CML CD34+ cells markedly reduced their clonogenic potential and growth factor-mediated cell proliferation but favored higher frequency of BCR-ABL-free colonies. In conclusion, these data show that 5-FU-resistant CD34+ cells from the PB of CML patients contain normal progenitor cells, which can be selected and expanded in short-term cytokine-mediated cultures.
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PMID:5-Fluorouracil-resistant CD34+ cell population from peripheral blood of CML patients contains BCR-ABL-negative progenitor cells. 854 39

A human myeloid leukemia cell line, KBM-7, was developed from a patient in the blastic phase of chronic myeloid leukemia (CML). We characterized its morphology, immunophenotype, cytogenetics, and proliferative capacity. Developed in the absence of exogenous lymphokines, KBM-7 in vitro cloning capacity actually decreased when colony-stimulating factors were added. The cells had an aberrant immature myeloid phenotype, a doubling time of 22 h in suspension cultures and a high cloning efficiency in semisolid system (24 +/- 3)%. Early passages contained one near-haploid (predominant) and one hyperdiploid stem line. Gradually the hyperdiploid stem line became predominant, reaching an average of 49 chromosomes per cell. Cells from passage 89 had two Philadelphia chromosomes [t(9;22)(q34;q11)] and lacked normal copies of chromosomes 9 and 22. Detailed molecular characterization of the breakpoint in the t(9;22)(q34;q11) revealed that KBM-7 had the BCR 2/ABL II splice junction. The cells had high protein kinase (p210BCR-ABL) activity and carried two identified variants of an ABL-BCR message. There was no evidence that normal BCR or c-ABL messages were expressed, assessed with the reverse-transcriptase polymerase chain reaction. When KBM-7 cells were heterotransplanted into nude mice without immunosuppressive pretreatment, one of three mice injected with 1 x 10(7) cells and all mice injected with 1 x 10(8) cells developed slowly growing granulocytic sarcomas within 6-8 weeks. These tumors were locally invasive but did not metastasize. We conclude that the KBM-7 cell line will be of value for investigating molecular events underlying neoplastic transformation in CML, in particular for studying the effects of BCR-ABL and ABL-BCR on the proliferation of CML cells in the absence of normal BCR and c-ABL messages.
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PMID:KBM-7, a human myeloid leukemia cell line with double Philadelphia chromosomes lacking normal c-ABL and BCR transcripts. 860 23

Reverse transcriptase-polymerase chain reaction (RT-PCR) has shown promise as a means of detecting low levels of cells bearing the Philadelphia chromosome (Ph1) and for detecting cytogenetically inapparent ("masked") Ph1 in patients with chronic myelogenous leukemia (CML). For detection by karyotyping, dividing cells must be used, precluding use of peripheral blood samples in cases with low peripheral blood blast counts. Reverse transcriptase-polymerase chain reaction was performed in 83 bone marrow and 30 peripheral blood samples from patients with CML to compare results with karyotyping and to evaluate utility of this test on peripheral blood samples. Using isolated total cellular RNA and a single primer pair, cDNA was transcribed, amplified, electrophoresed, and probed for bcr/abl fusion involving M-bcr exons 2 and 3 of the bcr gene. Fifty-three samples were from untreated or conventionally treated patients (pre-BMT), and 60 were from patients who had undergone bone marrow transplantation (post-BMT). Fifty of 53 pre-BMT samples were positive by RT-PCR. Two samples, negative by RT-PCR, had complex translocations, t(9;16;22) and t(4;14;22). One case was indeterminate by RT-PCR, but positive on retesting. Forty-five of 53 had Ph1 by karyotyping; 8 were negative, including 5 peripheral blood samples, 2 bone marrow samples with "masked" Ph1, and 1 bone marrow sample with poor growth. Thirty-five of 60 post-BMT samples were positive by RT-PCR. Fourteen of 60 post-BMT samples had Ph1 by karyotyping. Of the RT-PCR+/Ph1- cases, most showed a weak but definite band by RT-PCR, suggesting a low level of the bcr/abl fusion gene. Nineteen patients had concurrent peripheral blood and bone marrow samples analyzed by RT-PCR and karyotyping. Of 16 patients with satisfactory RNA extraction, 15 had concordant results by RT-PCR. Five patients had adequate metaphase cells for karyotypic analysis. All had Ph1 in bone marrow, but were negative in peripheral blood. Our results indicate that RT-PCR for detection of bcr/abl fusion is more sensitive than karyotyping in pre- and post-BMT samples. Furthermore, RT-PCR can be successfully performed on peripheral blood, yielding excellent correlation with bone marrow samples.
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PMID:Reverse transcriptase-polymerase chain reaction for bcr/abl fusion in chronic myelogenous leukemia. 865 51


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