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PubMed2003

Quantitative real-time reverse-transcription polymerase chain reaction for diagnosis of BCR-ABL positive leukemias and molecular monitoring following allogeneic stem cell transplantation.

Real-time reverse-transcription polymerase chain reaction (RT-PCR) (qPCR) of the BCR-ABL mRNA is a suitable technique to measure the amount of circulating leukemic cells in chronic myelogenous leukemia (CML). In this study, we evaluated a BCR-ABL-specific qPCR method using the LightCycler technology in 95 patients with Philadelphia chromosome positive acute leukemia (n = 7) or CML in different stages (n = 88). Primers and hybridization probes were chosen to detect the most prevalent variants of BCR-ABL (b2a2, b3a2, b2a3, b3a3, e19a2, e1a2) with a sensitivity of 10-5 for b2a2 and b3a2. With median BCR-ABL/G6PDH ratios of 10.7% in the untreated chronic phase, 43.2% in the newly diagnosed accelerated phase, and 131.4% in newly diagnosed blast crisis the BCR-ABL mRNA levels varied significantly between different stages of CML whereas no difference was found between blast crisis and untreated acute leukemias (136.9%). There was a strong relationship between qPCR results and cytogenetics in patients treated with imatinib, interferon-alpha, or following allografting. Thirteen patients with CML were sequentially examined by qPCR following myeloablative or non-myeloablative allogeneic peripheral blood stem cell transplantation. Five patients received donor lymphocytes and became BCR-ABL negative as confirmed by nested RT-PCR. The gradual disappearance of BCR-ABL positive cells could be monitored by qPCR following non-myeloablative transplantation. Comparison of BCR-ABL levels with the degree of donor chimerism showed that 91% of samples with complete donor chimerism were BCR-ABL negative. In 22% of BCR-ABL negative samples chimerism between 71% and 98% was observed, indicating the persistence of normal recipient's hematopoietic cells. In conclusion, the qPCR protocol used in this study is a reliable and fast method for monitoring molecular response in CML.

Antineoplastic Agents↗
PubMed1999

Strongly Polarized Optical Afterglows of Gamma-Ray Bursts.

The optical afterglows of the gamma-ray bursts can be strongly polarized, in principle up to tens of percents, if (1) the afterglow is synchrotron radiation from an ultrarelativistic blast, (2) the blast is beamed during the afterglow phase, i.e., the shock propagates within a narrow jet, (3) we observe at the right time from the right viewing angle, and (4) magnetic fields parallel and perpendicular to the jet have different proper strengths.

Journal Article↗
PubMed2000

Chandra X-Ray Observatory Arcsecond Imaging of the Young, Oxygen-rich Supernova Remnant 1E 0102.2-7219.

We present observations of the young, oxygen-rich supernova remnant 1E 0102.2-7219 taken by the Chandra X-Ray Observatory during its orbital activation and checkout phase. The boundary of the blast-wave shock is clearly seen for the first time, allowing the diameter of the remnant and the mean blast-wave velocity to be determined accurately. The prominent X-ray bright ring of material may be the result of the reverse shock encountering ejecta; the radial variation of O vii versus O viii emission indicates an ionizing shock propagating inward, possibly through a strong density gradient in the ejecta. We compare the X-ray emission with Australia Telescope Compact Array 6 cm radio observations (Amy & Ball) and with archival Hubble Space Telescope [O iii] observations. The ring of radio emission is predominantly inward of the outer blast wave, which is consistent with an interpretation of synchrotron radiation originating behind the blast wave but outward of the bright X-ray ring of emission. Many (but not all) of the prominent optical filaments are seen to correspond to X-ray bright regions. We obtain an upper limit of approximately 9x1033 ergs s-1 (3 sigma) on any potential pulsar X-ray emission from the central region.

Journal Article↗
PubMed2004

Expression of angiogenic factors in chronic myeloid leukaemia: role of the bcr/abl oncogene, biochemical mechanisms, and potential clinical implications.

Chronic myeloid leukaemia (CML) is a stem cell disease characterized by an increased production and accumulation of clonal BCR/ABL-positive cells in haematopoietic tissues. The chronic phase of CML is inevitably followed by an accelerated phase of the disease, with consecutive blast crisis. However, depending on genetic stability, epigenetic events, and several other factors, the clinical course and survival appear to vary among patients. Recent data suggest that angiogenic cytokines such as vascular endothelial growth factor (VEGF), are up-regulated in CML, and play a role in the pathogenesis of the disease. These factors appear to be produced and released in leukaemic cells in patients with CML. In line with this notion, increased serum-levels of angiogenic growth factors are measurable in CML patients. In this study we provide an overview of angiogenic growth factors expressed in CML cells, discuss the possible pathogenetic role of these cytokines, the biochemical basis of their production in leukaemic cells, and their potential clinical implications.

Angiopoietin-1↗
PubMed1976

Blast crisis of chronic myeloid leukaemia (CML). I. Presentation simulating acute lymphoid leukaemia (ALL).

Seven patients presenting as an acute leukaemia caused difficulty in diagnosis. The lymphoid appearance of the balst cells either initially or during treatment suggested acute lymphoid leukaemia (ALL). In each case the Philadelphia chromosome was shown to be present thus suggesting that these cases were examples of chronic myeloid leukaemia (CML) presenting in blast crisis without a detectable chronic phase. The implications of these findings are discussed and the difficulty in achieving a precise diagnosis in the acute leukaemias is emphasised. Cytogenetic analysis should be carried out whenever the type of acute leukaemia present is of critical importance.

Adolescent↗
PubMed1988

Cytogenetic studies of haemopoietic colonies from patients with an initial diagnosis of acute lymphoblastic leukaemia.

For patients with an initial diagnosis of Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukaemia (ALL) and no documented history of Ph1-positive chronic myeloid leukaemia (CML), the cell of origin and extent of lineage involvement of the disease is often unclear. This is largely due to the fact that cytogenetic analysis of direct marrow preparations cannot distinguish between the presence of Ph1-positive myeloid metaphases and infiltration of the marrow with dividing Ph1-positive blasts. Cytogenetic analysis of cultured haemopoietic colonies allows more precise lineage assignment. We have used this approach to study five adult patients who presented with Ph1-positive ALL and subsequently showed a significant increase in normal metaphases (to 18-100% of all metaphases examined) following remission induction. In four of these five patients, some Ph1-positive erythroid and granulopoietic cells could be demonstrated. In the other, as in three patients with childhood ALL who presented with a Ph1-negative but cytogenetically abnormal clone, only chromosomally normal erythroid and granulopoietic progenitors were detected. Two Ph1-positive CML patients who entered a lymphoid blast crisis following a recognized chronic phase were also studied. In both of these latter two patients all erythroid and granulocyte-macrophage colonies analysed were Ph1-positive. These findings support the concept that patients presenting with Ph1-positive ALL comprise a heterogeneous group. In some cases the disease may arise in a restricted lymphopoietic cell not capable of myelopoietic differentiation. However, in others involvement of myeloid cells suggests these may be variant forms of CML in spite of an unusual initial response of the Ph1-positive clone to therapy.

Adult↗
PubMed1999

Transcripts of immunoglobulin germline mu: an amplified myeloid and B-lymphoid common gene program in various leukemias.

To investigate the clinical implications of germline C mu transcription, the splice region between the 3' end of the enhancer and the first exon of immunoglobulin germline mu; was analyzed by RT-PCR in 63 samples from 59 patients with leukemia. Immunophenotypes of 33 samples from patients with acute leukemia were analyzed using a panel of these monoclonal antibodies: anti-immature/stem cell (HLA-DR, CD34); anti-mature myeloid (CD33, CD15); anti-T lymphoid (CD2, CD3, CD5, CD7, CD8), and anti-B lymphoid (CD10, CD19, CD20). Of the 63 samples, 33 (52%) contained germline C mu transcripts: 2/2 patients with chronic lymphocytic leukemia; 17/26 (65.4%) patients with acute myeloblastic leukemia; all 4 patients with chronic myelogenous leukemia in blast crisis and 1 in accelerated phase; 9/12 patients with acute lymphocytic leukemia. A clear correlation between germline transcripts and HLA-DR expression was observed among germline-positive cases (p < 0. 01). C mu expression and response to therapy clearly indicated that germline-mu-positive leukemia patients responded poorly to chemotherapy and had a worse clinical prognosis compared with C mu-negative patients (p < 0.01). After two courses of chemotherapy, 7/9 C mu-negative patients achieved complete remission compared to only 7/29 C mu-positive patients (p < 0.01). We conclude that the gene-regulating immunoglobulin germline C mu may be amplified in myeloid and B-lymphoid cells during leukemogenesis. Such genetic changes may be correlated with cellular terminal differentiation injury, resistance to chemotherapy and uncontrolled malignant cell proliferation.

Adolescent↗
PubMed1983

[The Münster study of intensive induction and consolidation therapy without maintenance therapy of acute myeloid leukemia. Results of 93 patients--cellular determinants for response and length of remission].

A 9-day high-dose 3-drug induction regimen including ARA-C, DNR, and TG at special time sequencing was given to 93 patients with AML, 15-74 (median 52) years old. After 1-2 courses for remission induction and, if possible, 2 identical courses of consolidation, no further therapy was applied during remission. Complete remission (CR) was achieved in 71% of all patients and in 74% of responders by 1 course only. Median remission duration is at 1 year with 13 patients in continuous CR for 13-38 (median 24) months. Patients completing consolidation reached a median remission duration of 22 months and those with rapid response to 1 induction course and with complete consolidation 38+ months. Patients monitoring included bone marrow DNA-histograms by flow cytometry, blood counts, percentage, and absolute number of blasts in bone marrow and LDH in serum. Among pretherapeutic parameters only LDH (inversely) correlated with CR duration. In contrast during early therapy rapid blast reduction, decrease of S-phase-index and of LDH as well as short recovery time of platelets and neutrophils predicted for low risk (when high risk included non-response and early relapse). Thus, monitoring of early cellular response parameters reflecting cellularity and proliferation seems to provide important individual determinants of therapeutic outcome.

Adolescent↗
PubMed2006

Platelet-derived growth factor-beta receptor activation is essential for fibroblast and pericyte recruitment during cutaneous wound healing.

Connective tissue remodeling provides mammals with a rapid mechanism to repair wounds after injury. Inappropriate activation of this reparative process leads to scarring and fibrosis. Here, we studied the effects of platelet-derived growth factor receptor-beta blockade in vivo using the platelet-derived growth factor receptor (PDGFR)-beta inhibitor imatinib mesylate on tissue repair. After 7 days, healing of wounds was delayed with significantly reduced wound closure and concomitant reduction in myofibroblast frequency, expression of fibronectin ED-A, and collagen type I. Using a collagen type I transgenic reporter mouse, we showed that inhibiting PDGFR-beta activation restricted the distribution of collagen-synthesizing cells to wound margins and dramatically reduced cell proliferation in vivo. By 14 days, treated wounds were fully closed. Blocking PDGFR-beta signaling did not prevent the differentiation of myofibroblasts in vitro but potently inhibited fibroblast proliferation and migration. In addition, PDGFR-beta inhibition in vivo was accompanied by abnormal microvascular morphogenesis reminiscent of that observed in PDGFR-beta-/- mice with significantly reduced immunostaining of the pericyte marker NG2. Imatinib treatment also inhibited pericyte proliferation and migration in vitro. This study highlights the significance of PDGFR-beta signaling for the recruitment, proliferation, and functional activities of fibro-blasts and pericytes during the early phases of wound healing.

Animals↗
PubMed1999

Biphenotypic (mixed myeloid/T-cell) extramedullary myeloid cell tumor.

A 32-year-old male with a 4-year history of chronic myelogenous leukemia (CML) in chronic phase for 4 years, then myeloid blast crisis for 7 months, developed diffuse bulky lymphadenopathy in association with a white blood count (WBC) of 17,100/mm3 with 70% blasts. Biopsy of a cervical lymph node revealed a blastic extramedullary myeloid cell tumor, which showed a biphenotypic (mixed myeloid/T-cell) immunophenotype. Chromosomal analysis revealed karyotypic features of both myeloid and lymphoid lineages. Although extramedullary myeloid cell tumor (EMT, granulocytic sarcoma, chloroma) is well known to occur in chronic myelogenous leukemia (CML), to our knowledge this is the first description of evolution of CML into a biphenotypic EMT.

Adult↗
PubMed1989

Further evidence that the site of the breakpoint in the major breakpoint cluster region (M-bcr) may be a prognostic indicator.

A break in chromosome 22 within the major breakpoint cluster region (M-bcr) is a characteristic of Philadelphia chromosome-positive CML. We have determined the zone of the breakpoint in 80 chronic myelogenous leukemia (CML) patients and have confirmed our previous observation that a relationship does exist between the subregion of the breakpoint within the M-bcr and the average length of the chronic phase of the disease. Patients with a 3' breakpoint have a statistically shorter chronic phase (25 months) than patients with a 5' break (55 months). Thus, a molecular analysis of the M-bcr may provide a prognostically useful indicator of the probable length of the chronic phase, although the underlying mechanism of blast transformation, and the role (if any) of the hybrid phl-abl mRNA, is still unclear.

Blast Crisis↗
PubMed1976

Studies on J chain and binding site for secretory component in circulating human B cells. II. The cytoplasm.

About 0-3-1-1% of the lymphoid cells from peripheral blood of healthy adults contained cytoplasmic immunoglobulin (Ig). The class distribution of these B cells varied greatly among individuals, with a preponderance of the IgA (26-65%) or the IgG (15-66%) class. A remarkably high percentage of the Ig-containing cells were positive for cytoplasmic J chain regardless of the class (100% for IgM, 87-97% for IgA, 50-100% FOR IgD, and 43-88% for IgG cells). This feature probably reflects that the cells represent circulating blasts derived from the early expansion phase of B-cell clones. The antigenic determinants of the J chain were in most IgA-containing cells considerably masked, indicating that this subunit was "correctly" arranged in the IgA dimers at the cytoplasmic level in the manner demonstrated for intestinal IgA plasma cells.

Adult↗
PubMed1982

Allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic or accelerated phase.

Eight patients with Ph1-positive chronic myelogenous leukemia (CML) in chronic or accelerated phase received high-dose cyclophosphamide, total body irradiation, and bone marrow transplantation from an HLA-identical sibling donor. All patients had prompt engraftment and achieved complete hematologic remission. Six patients remain alive and in continuous remission with a normal bone marrow karyotype 3-20+ mo posttransplant. One patient died from cytomegalovirus interstitial pneumonitis. Only one patient who was transplanted in accelerated phase relapsed 6.5 mo posttransplant and died in blast crisis. High-dose combined modality therapy is capable of producing sustained complete remissions in patients with CML treated during chronic or accelerated phase.

Adult↗
PubMed1994

Mutations of the N-ras gene in juvenile chronic myelogenous leukemia.

Juvenile chronic myelogenous leukemia (JCML), a myeloproliferative disorder of childhood, is distinct from adult-type chronic myelogenous leukemia (CML) and bears resemblance to chronic myelomonocytic leukemia (CMMoL). Since mutations in the N-ras gene have been found at high frequencies in CMMoL, but only rarely in CML, we analyzed mutations activating the N-ras gene in 20 patients with JCML. We used the strategy for analysis of gene mutations based on in vitro DNA amplification by polymerase chain reaction (PCR) followed by single-strand conformation polymorphism (SSCP) analysis and/or direct sequence analysis. Nucleotide sequence analysis showed single nucleotide substitutions involving codons 12, 13, or 61 in six of 20 patients (30%). Four of six patients with mutations were in chronic phase and the other two in blast crisis, indicating no apparent correlation with disease stage. Most of the patients with mutations were in the older age group with poor prognosis, although one patient in the younger age group also harbored the mutation. These data suggest that N-ras gene mutations may be involved in the pathogenesis and/or prognosis of JCML and provide further evidence that JCML is an entity distinct from CML.

Base Sequence↗
PubMed1993

Molecular characterization of a variant Ph1 translocation t(9;22;11) (q34;q11;q13) in chronic myelogenous leukemia (CML) reveals the translocation of the 3'-part of BCR gene to the chromosome band 11q13.

We performed cloning and sequence analysis of translocation junctions at 11q- and 22q- (Ph1) chromosomes and the corresponding germline DNAs of a variant Ph1-positive CML with t(9;22;11)(q34;q11;q13). Southern blot analysis using probes for different regions of bcr mapped the translocation break near the 5'-side of bcr exon 4. Cloning, Southern blot analysis and restriction map analysis of both bcr fragments showed that the part of bcr 3'- to the translocation break moved to 11q13. Sequence analysis of the translocation junction on the Ph1 chromosome showed that the translocation break occurred 63 bp upstream of exon 4. Compared to the germline sequence, bcr sequence from the translocated partners showed deletion of seven basepairs at the site of translocation. A probe derived from the 5'-region of the clone isolated from the 11q- chromosome identified clonal rearrangements in the leukemic DNA. Restriction map and sequence analysis showed that this clone consisted of the 3'-half of the glutathione S-transferase Pi (GST-Pi) gene and the 3'-part of bcr. We identified two point mutations in the GST-Pi allele involved in translocation. Northern blot analysis showed that the GST-Pi gene was expressed in the leukemic cells at blast crisis but not at chronic phase; however, no fusion mRNA between GST-Pi and bcr was identified. We did not find any sequence homology between 11q13 DNA and 22q11 DNA around the translocation breakpoints; however, sequences homologous to ALU repeats were identified close to the sites of translocation breaks at 22q11 and 11q13. This study supports our hypothesis that variant Ph1 translocations may occur as primary cytogenetic changes similar to the classical Ph1 translocations.

Base Sequence↗
PubMed1993

Immunophenotypic characteristics of blast crisis of chronic myeloid leukaemia: correlations with clinico-biological features and survival.

Blast cells from 40 patients with Philadelphia-positive chronic myeloid leukaemia (CML) in blast crisis were analysed by immunophenotypic methods. In 27 cases, BCR gene studies were also performed. By light microscopy morphology and cytochemistry the cases were classified as follows: undifferentiated (n = 7; 17.5%), myeloid (n = 27; 67.5%), and lymphoid (n = 6; 15%). On the basis of the immunological markers, the cases were reclassified as: myeloid (n = 17; 42.5%), megakaryoblastic (n = 17; 42.5%), and lymphoid (n = 6; 15%). The seven cases initially considered as undifferentiated by morphological and conventional cytochemical criteria were classified as myeloid (four cases) and megakaryoblastic (three cases) by marker analysis. The monoclonal antibody anti-myeloperoxidase (anti-MPO) was the most sensitive myeloid associated marker in these cases, being positive in five of them. A significant proportion (27%) of non-lymphoid blast crisis cases were CD7-positive, and myeloid markers were positive in the four lymphoid CML-CB cases studied. Analysis of the clinico-haematological characteristics on the various subgroups of patients showed that patients with lymphoid blast crisis had shorter duration of the chronic phase, more frequent extramedullary blastic involvement, more favourable response to therapy, and longer survival. Finally, a trend for an association between megakaryoblastic involvement of blast crisis and breakpoint localization in the 3' extreme of the M-bcr segment was also noted.

Adolescent↗
PubMedDate not supplied

Potential clinical applications of rhGM-CSF in acute myeloid leukemia based on its biologic activity and receptor interaction.

BACKGROUND AND OBJECTIVE: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multilineage hemopoietic growth factor that stimulates proliferation, differentiation, and survival of progenitor cells, enhances the functional activities of mature myeloid effector cells, and plays a key role in host defense and the inflammatory process. Although the clinical use of rhGM-CSF in patients affected by lymphoid malignancies is widely accepted, its utility and safety in the management of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is still controversial. The three main schedules adopted for clinical application of GM-CSF in AML are as follows: A) post-chemotherapy, in order to shorten the duration of neutropenia and/or monocytopenia; B) prechemotherapy to recruit blast cells into active cell cycle phases, and to increase their sensitivity to cell cycle-dependent cytotoxic drugs; C) as a mobilizing agent to induce the release of progenitor cells from bone marrow into circulation (peripheral blood progenitor cell transplantation-PBPC). The objective of this paper is to analyze the potential clinical applications of rhGM-CSF in AML. EVIDENCE AND INFORMATION SOURCES: The material examined in the present review includes several personal papers in this field and articles and abstracts published in journals covered by the Science Citation Index. STATE OF THE ART: Based on current knowledge, it may be argued that rhGM-CSF should be used only in a subset of AML patients at high risk of infection mortality, including elderly subjects, and/or in those AML patients who relapse or are resistant to induction treatment. However, the risk of stimulating the leukemic clone following GM-CSF therapy should be kept in mind when using this growth factor in the clinical setting, even though the great majority of the reported papers on this subject have shown that GM-CSF therapy does not affect relapse rates, frequency of remissions or patient life expectancy. PERSPECTIVES: It is likely that new data from controlled clinical trials will clarify the therapeutic role of GM-CSF in myeloid-derived malignancies, allowing the establishment of consensus guidelines for its use.

Acute Disease↗
PubMed1996

[Mast cell leukemia evolved from RAEB-T (5q-syndrome) in a 12 year-old girl].

A 12-year-old, female 5q- syndrome case of refractory anemia with excess of blasts in transformation (RAEB-T) evolving to mast cell leukemia is described. This case was admitted because of general fatigue, when her peripheral blood count revealed anemia and leukocytosis with basophil-like cells. RAEB-T was diagnosed based on the laboratory findings of her peripheral blood and bone marrow aspiration, which revealed over 10% peripheral blast cells and dysmyelopoietic changes in all three lineages. Chromosomal analysis of the bone marrow cells showed 46, XX, 5q-. Six months later, the RAEB-T phase evolved to acute leukemia, despite prednisolone, vitamin D3, oxymetholone and low-dose cytosine arabinoside treatment. She had remarkable pancytopenia, hemorrhage, and hepatosplenomegaly, which were not responsive to daunomycin, enocitabine, etoposide, and 6-mercaptopurine, and eventually died. This case was unique in that her karyotype changed to normal; 46, XX, and her blast cells were mast cell lineage during the overt leukemic phase. Interestingly, some blasts were intermediate cells possessing the ultrastructural features typical of both basophils and mast cells.

Anemia, Refractory, with Excess of Blasts↗