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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to analyze the efficiency of interphase FISH for the detection and monitoring of Ph+ cells in chronic myelogenous leukemia (CML) under interferon (IFN) treatment, the following experiments were performed: (1) 98 specimens derived from 32 patients were analyzed in parallel by dual-color FISH and by conventional chromosome analysis (CCA). A 300/200 kb BCR/ABL probe was used in all tests and a smaller 35.5/39 kb probe was tested in parallel in 22 BM samples; (2) 30 BM samples were prepared by direct harvest and by 24-h culture and were analyzed in parallel; (3) PB and BM samples obtained simultaneously from 11 patients were analyzed. The cut-off point for the recognition of BCR/ABL fusion was set at 2.4%, calculated as the mean percent of false positivity in 11 controls plus 3 s.d. A very close correlation was observed (r=0.994, r2=0.988, P < 0.0001) between the percentages of Ph+ cells as assessed by CCA and by interphase FISH in 98 samples (26 at diagnosis). There was a moderate overestimation of the frequency of Ph+ cells by FISH with respect to CCA, that was more evident at low-to-medium values of Ph positivity. Seven specimens without Ph+ metaphases (17-50 cells analyzed) were shown to carry 2.5-8% interphase cells with BCR/ABL fusion. Similar percentages of BCR/ABL+ nuclei were recorded in 22 samples hybridized using the 300/200 kb and the 35.5/39 kb probe-sets (variation range: 0-5%, mean 2.3%). A very good correlation between the frequency of Ph+ interphase cells was observed when analyzing in parallel BM preparations after direct harvest and after 24-h culture. Underestimation of the percentage of BCR/ABL+ cells was noted to occur in 2/11 PB samples, compared to BM samples, the remaining nine cases showing superimposable results at either sites. We arrived at the following conclusions: (1) dual-color FISH enables an accurate detection and monitoring of the size of the Ph-positive clone in CML at diagnosis and after IFN-therapy; (2) FISH is more accurate than CCA, especially at low levels of Ph-positive cells; (3) testing of directly harvested BM samples is feasible and accurate, giving the opportunity to perform centralized FISH analysis in the context of multicentre trials; (4) the percentage of BCR/ABL+ PB cells usually, though not invariably, reflects the frequency of mutated cells in the BM.
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PMID:Fluorescence in situ hybridization for the detection and monitoring of the Ph-positive clone in chronic myelogenous leukemia: comparison with metaphase banding analysis. 982 46

Chronic myeloid leukemia (CML) is thought to arise from a pluripotent hematopoietic stem cell that has undergone a reciprocal translocation between the BCR gene on chromosome 22 and the ABL proto-oncogene on chromosome 9. This rearrangement results in a shortened chromosome 22, designated the Philadelphia (Ph) chromosome. The Ph chromosome has been found in cells from all hematopoietic lineages except mature T lymphocytes. To examine this issue, we combined fluorescence-activated cell sorting (FACS) and fluorescence in situ hybridization (FISH) to study lineage involvement of mature cells and stem cells in 12 patients with CML in the chronic phase. We found Ph chromosomes in myeloid cells and most B lymphocytes (CD19(+)) but not in mature T cells (CD3(+)) or natural killer (NK) cells (CD3(-)56(+)). Moreover, evidence of BCR/ABL fusion was found in pluripotent stem cells (CD34(+)Thy-1(+)), B-progenitor cells (CD34(+)CD19(+)), T/NK progenitor cells (CD34(+)CD7(+) cells), and T progenitor cells (CD34(+)CD7(+)CD5(+)) with a frequency equal to that in all CD34(+) cells isolated by FACS from bone marrow cells. T lymphocytes showed a marked decrease in Ph+ cells between progenitor cells and mature cells. Moreover, the ratios of Ph+ to Ph- cells in mature T cells and NK cells were below background levels, whereas Ph+ B lymphocytes also decreased during their maturation. These data suggest that Ph+ lymphocytes are eliminated during differentiation. In contrast to FISH of blood and bone marrow, which gives information principally about mature cells, the technique of "sorter FISH (FACS + FISH)" provides a powerful tool to explore the cytogenetic changes in immature cell populations of stem cell diseases based on immunophenotypes. Further clarification of genetic changes in stem cells could be achieved by using sorter FISH with monoclonal antibodies.
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PMID:Lineage involvement of stem cells bearing the philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. 984 42

Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoietic stem cell of the bone marrow and is characterized by greatly increased numbers of granulocytes in the blood. Myeloid and other hematopoietic cell lineages are involved in the process of clonal proliferation and differentiation. After a period of 4-6 years the disease progresses to acute-stage leukemia. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. Most of ABL is linked with a truncated BCR. The BCR/ABL fusion gene codes for an 8-kb mRNA and a novel 210-kDa protein which has higher and aberrant tyrosine kinase activity than the normal c-ABL-coded counterpart. Phosphorylation of a number of substrates such as GAP, GRB-2, SHC, FES, CRKL, and paxillin is considered a decisive step in transformation. An etiological connection between BCR/ABL and leukemia is indicated by the observation that transgenic mice bearing a BCR/ABL DNA construct develop leukemia of B, T, and myeloid cell origin. CML cells proliferate and expand in an almost unlimited manner. Adhesion defects in bone marrow stromal cells have been proposed to explain the increased number of leukemic cells in the peripheral blood. However, findings of our laboratory have shown that the BCR/ABL chimeric protein that is expressed in transfected cells may, under certain conditions, also increase the adhesion to fibronectin via enhanced expression of integrin. Our previous immunocytological studies on the expression of beta1 and beta2 integrins have found no qualitative differences between normal and CML hematopoietic cells in vitro. Even long-term-cultured CML bone marrow or blood cells continuously express those adhesion molecules that are characteristic of the cytological type. Recent experiments indicate that certain early CML progenitors may adhere to the stromal layer in vitro similarly to their normal counterparts. They cannot be completely removed by long-term culture on allogeneic stromal cells. At present, the only curative therapy is transplantation of allogeneic hematopoietic stem cells. Based on the molecular and cellular state of knowledge of CML, new therapies are being developed. BCR/ABL antisense oligonucleotides, inhibitors of tyrosine kinase, peptide-specific adoptive immunotherapy or peptide vaccination, and restoration of hematopoiesis by autologous stem cell transplantation following CML cell purging are examples of important approaches to improving CML treatment.
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PMID:Chronic myelogenous leukemia: molecular and cellular aspects. 987 25

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder that is characterized by splenomegaly and marked elevation of the blood leukocyte count with granulocyte in maturity. Ph chromosome was identified in CML in 1960 and was found to clearly result from reciprocal translocation between chromosome 9 and chromosome 22 (t(q;22)) (q34;q11). CML arises from a single pluripotent hematopoietic stem cell with the Ph chromosome and demonstration of the Ph chromosome in blood or marrow cells establishes and unequivocal diagnosis of CML. The Ph chromosome is recognized as the cytogenetic result of a rearrangement of the ABL gene on chromosome 9 and the BCL gene on chromosome 22, which leads to the creation of a BCR/ABL fusion gene on chromosome 22. Abnormal ABL-related protein with increased tyrosine kinase activity suggested a molecular mechanism of CML. The BCR/ABL fusion gene can be found not only in the chromosome but in interphase nuclei by fluorescence in situ hybridization (FISH). We employed both fluorescence activated cell sorter (FACS) and FISH to study the lineage involvement of individual stem cells and progenitor cells in patients with CML. Evidence of BCR/ABL fusion was found in pluripotent stem cells (CD34+, Thy1+), myeloid cells, B progenitor cells (CD34+, CD19+) and T/NK progenitor cells (CD34+, CD7+, CD5+) but not mature T cells (CD3+) or natural killer cells (CD3-, CD56+). These data suggested that BCR/ABL gene fusion occurs in pluripotent stem cells and that Ph+ T cells and natural killer cells are eliminated during differentiation.
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PMID:[Progress in laboratory medicine in chronic myeloid leukemia]. 991 8

The hallmark of chronic myelogenous leukemia (CML) is the Philadelphia (Ph) chromosome that fuses genetic sequences of the BCR gene on chromosome 22 with c-ABL sequences translocated from chromosome 9. BCR/ABL fusion proteins have a dysregulated protein tyrosine kinase (PTK) activity exerting a key role in malignant transformation. Targeting the tyrosine kinase activity of BCR/ABL or using agents capable of triggering apoptosis might represent attractive therapeutic approaches for ex vivo purging. AG957, a member of the tyrphostin compounds, exerts a selective inhibition of p210(BCR/ABL) tyrosine phosphorylation. We report here that preincubation of CML or normal CD34(+) cells with graded concentration of AG957 (1 to 100 micromol/L) resulted in a statistically significant, dose-dependent suppression of colony growth from multipotent, erythroid, and granulocyte-macrophage progenitors as well as the more primitive long-term culture-initiating cells (LTC-IC). However, AG957 doses causing 50% inhibition (ID50) of CML and normal progenitors were significantly different for multilineage colony-forming units (CFU-Mix; 12 v 64 micromol/L; P =.008), burst-forming unit-erythroid (BFU-E; 29 v 89 micromol/L; P =.004), colony-forming unit-granulocyte-macrophage (CFU-GM; 34 v 85 micromol/L; P =.004), and LTC-IC (43 v 181 micromol/L; P =.004). In 5 of 10 patients, analysis of BCR/ABL mRNA on single progenitors by reverse transcription-polymerase chain reaction showed that AG957 at 50 micromol/L significantly reduced the mean (+/-SD) percentage of BCR/ABL-positive progenitors (92% +/- 10% v 33 +/- 5%; P =.001). Because AG957 treatment resulted in significantly higher percentages of apoptotic cells (30% v 9%) in the BCR/ABL-transfected 32DLG7 cells as compared with 32D-T2/93 cells (BCR/ABL-negative), we investigated the combined effects of AG957 with the anti-Fas receptor (Fas-R) monoclonal antibody CH11 that triggers apoptosis. As compared with AG957 alone, the sequential treatment of CML CD34(+) cells with AG957 (1 micromol/L) and CH11 (1 microgram/mL) increased CFU-Mix, BFU-E, and CFU-GM growth inhibition by 1.6-fold, 3-fold, and 4-fold, respectively. In contrast, the treatment of normal CD34(+) cells with AG957 and CH11 failed to enhance AG957-induced colony growth inhibition. We conclude that (1) AG957 inhibits in a dose-dependent manner CML CD34-derived colony formation by both primitive LTC-IC as well as committed CFU-Mix, BFU-E, and CFU-GM; (2) this growth inhibition is associated with the selection of a substantial amount of BCR/ABL-negative progenitors; and (3) the antiproliferative effect of AG957 is dramatically increased by combining this compound with the anti-Fas-R antibody CH11. These data may have significant therapeutic applications.
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PMID:Effects of the tyrosine kinase inhibitor AG957 and an Anti-Fas receptor antibody on CD34(+) chronic myelogenous leukemia progenitor cells. 1033 7

We report a chronic myeloid leukemia patient without evidence of a Philadelphia (Ph) chromosome in whom RT-PCR analysis performed in blast crisis demonstrated the existence of both common b3a2 and b2a2 BCR/ABL fusion transcripts. In situ hybridization studies with BCR- and ABL-specific probes showed location of the BCR/ABL fusion gene on chromosome 9, band q34, instead of at chromosome 22q11, and that it resulted from an insertion of the 5' side of BCR within the ABL gene on chromosome 9. The vast majority of cells showed a BCR/ABL fusion gene on both chromosomes 9, which is equivalent to a double Ph chromosome, thus reinforcing the notion that the critical event in CML is the formation of a functional BCR/ABL fusion gene.
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PMID:Insertion of the 5' part of BCR within the ABL gene at 9q34 in a Philadelphia-negative chronic myeloid leukemia. 1052 30

The Philadelphia chromosome translocation t(9;22)(q34;q11) may give rise to different BCR/ABL fusion mRNAs due to different genomic breakpoints and alternative splicing. The e1a2, b2a2 or b3a2 and c3a2 fusion mRNAs encode distinct fusion proteins (p190, p210 and p230, respectively), which are associated with different forms of leukemogenesis in humans and animal models. Our patient presented with acute pre-B cell lymphoblastic leukemia (ALL) with normal cytogenetics. After 3 years of standard ALL therapy, he relapsed with t(9;22)-positive chronic myelogenous leukemia (CML). Retrospective molecular analyses of the pre-treatment pre-B cell ALL sample showed the b3a2 (p210) and e1a2 (p190) BCR/ABL fusion transcripts. Only the b3a2 (p210) transcript was detected at relapse. Southern and immunoglobulin heavy chain (IgH) analyses of the presentation and relapse samples revealed an identical BCR rearrangement in both samples. However, only the ALL sample harbored an IgH gene rearrangement. These findings show a clonal relationship between the more differentiated pre-B cell and less differentiated CML clones and that the p210 and p190 fusion mRNAs were alternatively spliced from a single genomic breakpoint. Our patient's unusual molecular findings provide circumstantial evidence that the p190 protein may promote a more differentiated phenotype in a comparatively less differentiated p210-transformed precursor cell.
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PMID:Pre-B acute lymphoblastic leukemia with b3a2 (p210) and e1a2 (p190) BCR-ABL fusion transcripts relapsing as chronic myelogenous leukemia with a less differentiated b3a2 (p210) clone. 1060 22

We encountered a 44-year-old woman with suspected chronic myelocytic leukemia (CML) in the acute phase that was difficult to be differentiate from Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). At disease onset, her bone marrow showed an increase in blasts that were negative for myeloperoxydase (MPO) and Positive for CD10, 19, 34, and HLA.DR. Standard type Ph was detected by chromosome analysis, and both major and minor BCR/ABL m-RNA were detected by reverse-transcriptase polymerase chain reaction (RT-PCR) methods. Neutrophil alkaliphosphatase (NAP) score was normal, and neither eosinophilia nor basophilia was observed in peripheral blood. Under a presumptive diagnosis of Ph-positive ALL (L2), the patient was given AdVP (doxorubicin, vincristine, and prednisolone) therapy followed by a regimen of LMVP (L-asparaginase, mitoxantrone, and VP), and obtained a complete remission 2 months later. At that time, FISH analyses of her bone marrow and blood cells no longer detected bone marrow Ph or BCR/ABL fusion gene. A month later, however, the leukemia relapsed with an increase in MPO-positive blasts in bone marrow, and the patient died soon thereafter. We finally concluded that her leukemia was not Ph-positive ALL, but CML in the acute phase at disease onset.
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PMID:[Blast crisis of chronic myelocytic leukemia that was difficult to differentiate from Ph+ acute lymphoblastic leukemia]. 1062 28

This report describes two cases of Philadelphia chromosome-negative (Ph(-)) non-Hodgkin's lymphomas (NHLs) recognized in patients with chronic phase Ph-positive (Ph(+)) chronic myelogenous leukemia (CML). Lymph node biopsy of patient 1 was initially diagnosed as diffuse large B cell non-Hodgkin's lymphoma (NHL, T cell rich variant), but at relapse showed immunoblastic features with a marked decrease of admixed lymphocyte components. Patient 2 presented with thickened parietal pleura which revealed a CD30-positive anaplastic large cell lymphoma showing null cell phenotype and genotype with abundant admixed neutrophils and lymphocytes. At the time of lymphoma diagnosis, the patients had CML for 33 and 10 months, respectively. DNA obtained from bone marrow cells at the time of lymphoma diagnosis showed BCR/ABL gene rearrangements by both Southern blot analysis and reverse transcription polymerase chain reaction (RT-PCR), but lacked both immunoglobulin and T cell receptor gene rearrangements. BCR gene rearrangement and BCR/ABL fusion gene were also identified in lymph node and pleural biopsies by Southern blot and RT-PCR analysis, respectively. However, both biopsy specimens also contained reactive lymphocytes and neutrophils, and no fusion signals between BCR and ABL genes were identified in the hyperdiploid lymphoma cells of either case by fluorescence in situ hybridization (FISH). These data suggest the lymphoma cells in both cases were not genetically associated with BCR/ABL. Therefore, these cases were not diagnosed as an extramedullary localized blast crisis in CML, but as Ph(-) NHLs. This represents the first definitive demonstration of peripheral B cell lymphoma occurring by a separate genetic pathway, lacking BCR/ABL, in patients with Ph(+) CML. A review of the literature identified two different subtypes of malignant lymphomas arising in patients with an antecedent or concurrent diagnosis of CML. The most common are T cell lymphomas displaying an immature thymic phenotype, while peripheral B cell lymphomas are more rare. Our study shows, however, that 'Ph(+) NHL' occurring in CML or acute lymphocytic leukemia (ALL) may represent an unrelated neoplasm, even if standard cytogenetic analysis reveals a Ph(+) chromosome, and that FISH is required to confirm whether a localized lymphoid neoplasm is either a true extramedullary localized blast crisis or genetically distinct neoplasm. Leukemia(2000) 14, 169-182.
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PMID:Ph-negative non-Hodgkin's lymphoma occurring in chronic phase of Ph-positive chronic myelogenous leukemia is defined as a genetically different neoplasm from extramedullary localized blast crisis: report of two cases and review of the literature. 1063 93

A case of chronic myeloid leukemia displaying an uncommon t(21;22)(q22;q11) is reported. For the first time, this translocation has been characterized by fluorescence in situ hybridization (FISH) and the reverse transcriptase polymerase chain reaction (RT-PCR). FISH, with the use of whole-chromosome painting probes and probes specific for the BCR and ABL genes, showed a three-way variant Philadelphia translocation (9;22;21)(q34;q11;q22) with a BCR/ABL fusion residing on the der(22). In addition, RT-PCR demonstrated a b2a3 BCR/ABL fusion transcript. Underlying mechanisms and prognostic implications are discussed.
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PMID:Chronic myeloid leukemia with a rare variant Philadelphia translocation: t(9;22;21)(q34;q11;q22). 1064 Jan 51


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