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PubMed1990

[Enzymatic markers in chronic myeloleukemia and their importance for identifying a blast crisis].

The paper summarizes data on the activity of adenosine deaminase and purine nucleoside phosphorylase which contribute to purine nucleotide degradation. The enzyme activity was studied in leukocytes of varying degree of differentiation obtained from 29 cases with chronic phase of chronic myeloid leukemia (CML), 19 patients with acute phase of the disease and from blasts of 32 cases with CML-associated blast crisis. In CML patients, lymphocytes of leukemic clones showed various levels of activity of the enzymes. Myeloid and lymphoid blast crises proved biochemically heterogeneous. The possibility to establish the nature of blast crisis in CML on the basis of profile of adenosine deaminase and purine nucleoside phosphorylase in blasts is discussed.

Adenosine Deaminase↗
PubMed1997

t(3;21) following peripheral blood stem cell transplantation in chronic phase chronic myeloid leukaemia.

A 40-year-old male with Ph-positive CML underwent PBSC autografting after initial treatment with hydroxyurea and interferon. Following autograft he remained in chronic phase with cytogenetic or molecular evidence of low levels of residual Ph-positive cells. However, additional cytogenetic abnormalities, including t(3;21) typically seen in therapy-related myelodysplastic syndrome (MDS) and AML and blast crisis of CML, developed as an independent cell line following the autograft. More than 4 years after the autograft, the patient remains in chronic phase with no evidence of accelerated phase or blast crisis of CML, but with a concurrent MDS. We report a case of CML who developed therapy-related MDS following PBSC autograft while still remaining in chronic phase.

Adult↗
PubMed1994

No evidence for microsatellite instability or consistent loss of heterozygosity at selected loci in chronic myeloid leukaemia blast crisis.

The aim of the present study was to investigate loss of heterozygosity (LOH) or microsatellite instability in chronic myeloid leukaemia (CML) blast crisis at genomic locations which are known or postulated to harbour tumour suppressor genes. We studied 48 patients in blast crisis of myeloid (n = 31), lymphoid (n = 15), megakaryocytic (n = 1), or mixed lineage (n = 1) phenotype by comparing constitutional DNA extracted from buccal epithelial cells or chronic phase leucocytes with DNA obtained from blast crisis leucocytes. Twelve variable number tandem repeat loci from six different chromosomes were amplified by polymerase chain reaction using labelled primers, and fractionated on polyacrylamide gels. After autoradiography, length as well as intensity of the amplified products were compared between constitutional and blast crisis samples. LOH was scored as complete, partial or none in informative patients. Complete LOH was found in one patient at 8p22 and another at 13q14; partial LOH was detected in three patients at 11p13 and/or 11p15. No LOH was found at 6q27, 8p21, 18q21, 22q11-12 and 22q13 in any patient. Furthermore, no consistent difference in allelic length was observed in 517 paired amplifications indicating no microsatellite instability. We conclude that the Rb gene at 13q14, the Wilms tumour gene at 11p13, the DCC gene at 18q21, the neurofibromatosis 2 gene at 22q11-13 and uncloned tumour suppressor genes at 6q27, 8p21-22 and 11p15, as well as genes responsible for microsatellite instability, are unlikely to be involved in the progression of CML to blast crisis in the majority of patients.

Blast Crisis↗
PubMed2005

Structural analysis of a set of proteins resulting from a bacterial genomics project.

The targets of the Structural GenomiX (SGX) bacterial genomics project were proteins conserved in multiple prokaryotic organisms with no obvious sequence homolog in the Protein Data Bank of known structures. The outcome of this work was 80 structures, covering 60 unique sequences and 49 different genes. Experimental phase determination from proteins incorporating Se-Met was carried out for 45 structures with most of the remainder solved by molecular replacement using members of the experimentally phased set as search models. An automated tool was developed to deposit these structures in the Protein Data Bank, along with the associated X-ray diffraction data (including refined experimental phases) and experimentally confirmed sequences. BLAST comparisons of the SGX structures with structures that had appeared in the Protein Data Bank over the intervening 3.5 years since the SGX target list had been compiled identified homologs for 49 of the 60 unique sequences represented by the SGX structures. This result indicates that, for bacterial structures that are relatively easy to express, purify, and crystallize, the structural coverage of gene space is proceeding rapidly. More distant sequence-structure relationships between the SGX and PDB structures were investigated using PDB-BLAST and Combinatorial Extension (CE). Only one structure, SufD, has a truly unique topology compared to all folds in the PDB.

Databases, Protein↗
PubMed1986

Cytogenetic studies in bone marrow transplant recipients.

Chromosome studies were performed in 24 patients who underwent allogeneic bone marrow transplantation (BMT) for severe aplastic anaemia (8), chronic myeloid leukemia (5 in chronic, 2 in accelerated phase and 1 in lymphoid blast crisis), acute myeloid leukemia (6), acute lymphoblastic leukemia in relapse (1) and Hodgkin's disease (1). Donor-cell type engraftment was demonstrated in 21 patients: in all 17 sex-mismatched transplants and - as demonstrated by reconstitution with Ph-negative cell populations - in 4 CML patients with a sex-matched donor. Recipient-type mitoses were seen in the bone marrow of 5 cases (1 SAA, 3 CML, 1 AML) after transplantation. They were only observed on one occasion in patients with SAA (4 of 25 on day 33) and AML (44 of 50 on day 14). Despite the continued demonstration of some Ph-positive mitoses in 3 patients with CML up to day 28, 323 and 451 after BMT, respectively, all surviving CML patients are still in complete haematological and clinical remission. So far the significance of these cytogenetically abnormal persisting host cells remains unknown.

Adolescent↗
PubMed1990

Analysis of the cellular DNA and RNA content in acute leukemias by flow cytometry.

In the present study bone marrow samples from 573 patients with newly diagnosed acute myeloid (AML) and lymphoblastic or undifferentiated leukemias (ALL/AUL), were analysed for their cellular DNA and DNA/RNA content, respectively, by means of flow cytometry. From 237 patients with AML 35.4% revealed aneuploid DNA stemlines. While no relation of DNA aneuploidy with other pretherapeutic parameters, including FAB subtype, white blood cell count, lactate dehydrogenase, S-phase index and percentage of blasts in the bone marrow, was observed, cases with aneuploid DNA stemlines revealed a tendency towards longer remission duration. In ALL/AUL 21.8% of 280 patients expressed DNA aneuploidies, which were less frequently found in T-cell ALL (11.1%) as compared to common(C)-ALL (21.4%) or null-cell(null)-ALL (23.5%). DNA aneuploidy was not related with other clinically defined risk factors such as age, white blood cell count, and rapid achievement of remission. Patients with DNA indices less than 1.0, however, tended to have shorter remissions. A significant difference in RNA indices was observed between AML and ALL/AUL with median values of 14.4 and 10.1, respectively (P less than 0.05). These data indicate the usefulness of flow cytometric analyses of cellular DNA and RNA content for the characterization and classification of acute leukemias, complementing the identification of clinical risk factors, immuno-phenotyping and cytogenetics.

Acute Disease↗
PubMed1991

Further evidence for the molecular heterogeneity of chronic myeloid leukemia.

Cytogenetic and molecular techniques were performed on samples obtained from 29 patients with chronic myelocytic leukemia (CML); 27 were in the chronic phase and two were in blast crisis. A further five cases were also analyzed, two with atypical CML (aCML), one with chronic neutrophilic leukemia (CNL), and two with juvenile CML (JCML). Most of the cases with typical CML were Philadelphia chromosome (Ph) positive and had a rearrangement within the major breakpoint cluster region (M-bcr). One of these cases was shown to be Ph positive but showed no rearrangement within the M-bcr. Two cases with clinical features typical of CML were Ph negative. One of these showed a rearrangement within the M-bcr, but no rearrangement was demonstrated in the other. Both patients in blast crisis were Ph positive and M-bcr positive. One showed a second Ph. Patients with aCML were Ph negative and had no M-bcr rearrangement. A polymorphism within the M-bcr was found with BglII in one case. No Ph chromosome or M-bcr rearrangement was found in CNL or JCML. These data support the molecular heterogeneity reported in CML.

Blast Crisis↗
PubMed1987

Utility of molecular genetic analysis of bcr rearrangement in the diagnosis of chronic myeloid leukemia.

Two DNA probes for the breakpoint cluster region (bcr) of chromosome # 22 have been used to determine the proportion of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) cases that can be diagnosed by Southern blot analysis. Studies on 17 normal individuals and 17 patients with lymphomas and leukemias (other than CML) indicated that for the restriction enzymes chosen, only expected germ line DNA bands were obtained. In contrast, novel DNA bands interpreted as being the product of translocation within the bcr region could be demonstrated in 31 of 31 cases of Ph-positive CML. One commercially available 1.2 kb bcr probe detected most cases of CML. Because of the frequent presence of deletion of part of the bcr region, however, a probe from the 5' end of bcr is essential to detect some cases. An analysis of the bcr breakpoints occurring in CML patients suggested a difference in the location of the breakpoints for the blast crisis patients versus chronic phase patients although the difference between these two groups was not statistically significant. It is concluded that bcr analysis provides a powerful aid in the diagnosis of CML. This technique is of particular merit in cases when cytogenetic analysis is inconclusive and has considerable potential for improved speed and sensitivity of diagnosis.

Chromosome Banding↗
PubMed1997

Heterogeneity in the expression of Fc gammaRIII in morphologically mature granulocytes from patients with chronic myeloid leukemia.

Morphologically mature granulocytes from patients with chronic myeloid leukemia exhibit a defect in receptor mediated endocytosis of FITC-conjugated heat-aggregated IgG. In our earlier studies, we have shown that transcripts for Fc gammaRII and Fc gammaRIII are lowered in CML granulocytes, while no such trend was seen for CD11b, CD18 and actin, the other molecules involved in this process. We have also shown by flow cytometry that the number of granulocytes expressing the Fc receptors on their surface is lowered in CML patients. In this report, we show that the lowered steady state level of the mRNA for the Fc receptors is due to their faster degradation and not due to any defect in transcription. A study of the expression of mRNA for Fc gammaRIII in morphologically mature CML granulocytes by in situ hybridization showed that there is heterogeneity in the expression of this receptor, with some cells positive for the message and some not. These results suggest that the Fc gammaRIII transcript reaches a stable RNA pool in only some of the granulocytes, whereas in the rest of the cells, it is probably degraded after it is transcribed and is therefore not detected. The Fc gammaRIII is probably one of the first antigens to be lost from the leukemic granulocyte surface during the transition of the disease from the chronic phase to the accelerated phase and finally to the blast crisis.

Antigens, Neoplasm↗
PubMed1999

Clinical use of streptolysin-O to facilitate antisense oligodeoxyribonucleotide delivery for purging autografts in chronic myeloid leukaemia.

Antisense oligodeoxyribonucleotides (ODN) targeted against the breakpoint in BCR-ABL mRNA will specifically decrease BCR-ABL mRNA, provided cells are first permeabilised with streptolysin-O (SL-O). We used 18-mer chimeric methylphosphonodiester: phosphodiester linked (4-9-4) ODN complementary to 9 bases either side of the BCR-ABL junction to purge harvests ex vivo in three CML patients who remained completely Ph positive after multiple chemotherapy courses. After CD34+ cell selection and SL-O permeabilisation, harvests were purged with 20 microM ODN. After purging, all individual CFU-GM colonies grown from the two b3a2 breakpoint cases remained positive for BCR-ABL mRNA. In contrast, all 24 colonies grown from the b2a2 breakpoint case were BCR-ABL mRNA negative. Patients were conditioned with busulphan 16 mg/kg. The initial post-transplant course was uneventful, although the time to return to 0.5 x 10(9)/l neutrophils was slow at 25-51 days. Both chronic phase patients remain in haematological remission at +724 and +610 days, although each has cytogenetic evidence of relapse. The b2a2 accelerated phase patient died of myeloid blast transformation at day +91. The present SL-O-facilitated ODN purging strategy appears to be without significant toxicity, and offers considerable improvements in ODN delivery to the cytosol.

Antigens, CD34↗
PubMed2002

Fate of chronic myeloid leukemia patients treated with allogeneic bone marrow transplantation or chemotherapy and/or interferon at a single center: long-term results.

From April 1981 to February 2000, 105 patients with chronic myeloid leukemia (CML) underwent BMT from HLA-identical related donors at a single center. Eighty-eight patients were in chronic phase (CP), 11 patients in accelerated phase and six patients in blast crisis. Ten of these patients received a second BMT (BMT2). Comparison of BMT in CP with chemotherapy and/or alpha-IFN (n=70) was also made. Patients were given cyclophosphamide (CY) and single-dose TBI (CYTBI, n=38) or busulfan (BU) and CY (BUCY, n=67). Overall 54 patients are alive and 52 of them are disease-free with a median follow-up of 11.3 (range 1.1-19.4) years. Ten-year disease-free survival (DFS) in CP patients was better after BUCY, 61% (95% CI, 47-68%) than after CYTBI, 41% (95% CI, 23-61%) (P=0.07). For 88 patients who received a transplant in CP, results were significantly improved when BMT was performed within 1 year after diagnosis (P=0.02) or at an age < or = 25 years old (P=0.01). Ten-year survival in patients who received BMT in CP was better than in patients treated with chemotherapy (56% vs 10%; P=0.0001) or alpha-IFN-based treatment (33%; P=0.09) with survival curves crossing at 4.2 years and at 4 years, respectively. The probability of DFS after BMT2 was 60% (95% CI, 26-87%). CP patients who received BMT after CYTBI had a higher probability of relapse and transplant-related mortality than patients receiving BUCY (53% and 58% vs 9% and 34%; P=0.002 and P=0.08, respectively). All but six patients are currently on no medication and have resumed all activities without any limitation. These long-term results confirm that allogeneic BMT is the only curative approach for CML patients and should be offered to all patients with a suitable donor as soon after diagnosis as possible.

Adolescent↗
PubMed2000

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias.

Leukemic blasts from patients with acute phase chronic myeloid leukemic and refractory acute myeloid leukemia are highly resistant to a number of cytotoxic drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria toxin (DT) with a (G4S)2 linker (L), expressed and purified the recombinant protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3 receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative cell lines based on assays of cytotoxicity using thymidine incorporation, growth in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to 680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming colonies in semi-solid medium (colony-forming units leukemia) > or =10-fold in 4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and 3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors (colony-forming unit granulocyte-macrophage) from five different donors treated and assayed under identical conditions showed intermediate sensitivity with three- to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic progenitors from a number of acute phase CML patients suggests that this agent could have therapeutic potential for some patients with this disease.

DNA Replication↗
PubMed2002

Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.

Antineoplastic Agents↗
PubMed2005

Identification of genes potentially involved in disease transformation of CML.

In patients with chronic myeloid leukemia (CML) who do not reach a (near) complete cytogenetic response, the disease progresses over several years from an indolent, chronic phase into a rapidly fatal blast crisis. Events that are responsible for this transformation process are largely unknown. To identify changes in gene expression that occurred during the course of the disease, we performed cDNA subtraction on sequentially stored peripheral blood mononuclear cell pellets, collected throughout the course of disease of a single CML patient. In total, 32 differentially expressed sequences were identified, of which 27 corresponded to known genes. On quantitative PCR, eight of these genes, YWHAZ, GAS2, IL8, IL6, PBEF1, CCL4, SAT and MMRN, showed comparable differential expression in additional CML patient samples. This set of genes can be considered as a starting point for further research on causes of disease transformation in CML and may lead to new targets in the treatment of resistant CML.

Apoptosis↗
PubMed2001

Characterization of stage progression in chronic myeloid leukemia by DNA microarray with purified hematopoietic stem cells.

Chronic myeloid leukemia (CML) is characterized by the clonal expansion of hematopoietic stem cells (HSCs). Without effective treatment, individuals in the indolent, chronic phase (CP) of CML undergo blast crisis (BC), the prognosis for which is poor. It is therefore important to clarify the mechanism underlying stage progression in CML. DNA microarray is a versatile tool for such a purpose. However, simple comparison of bone marrow mononuclear cells from individuals at different disease stages is likely to result in the identification of pseudo-positive genes whose change in expression only reflects the different proportions of leukemic blasts in bone marrow. We have therefore compared with DNA microarray the expression profiles of 3456 genes in the purified HSC-like fractions that had been isolated from 13 CML patients and healthy volunteers. Interestingly, expression of the gene for PIASy, a potential inhibitor of STAT (signal transducer and activator of transcription) proteins, was down-regulated in association with stage progression in CML. Furthermore, forced expression of PIASy has induced apoptosis in a CML cell line. These data suggest that microarray analysis with background-matched samples is an efficient approach to identify molecular events underlying the stage progression in CML.

AC133 Antigen↗
PubMed2002

Changes in the proteome associated with the action of Bcr-Abl tyrosine kinase are not related to transcriptional regulation.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease, the hallmark of which is the Bcr-Abl protein tyrosine kinase (PTK). Without intervention the disease progresses from a benign chronic phase to a rapidly fatal blast crisis. To identify the molecular mechanisms underlying disease progression we used two-dimensional gel electrophoresis on a model we have previously described using the expression of a conditional mutant of Bcr-Abl PTK in a multipotent stem cell line, FDCP-Mix. Long term exposure of FDCP-Mix cells to Bcr-Abl mimics disease progression in CML. Four major differences were observed as a consequence of long term exposure to the Bcr-Abl PTK compared with cells exposed short term. The proteins were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry-generated peptide mass fingerprint data and liquid chromatography-tandem mass spectrometry-generated sequence information. Leukotriene A4 hydrolase, an enzyme known to be deregulated in CML, was found to be up-regulated. Annexin VI, vacuolar ATP synthase catalytic subunit A, and mortalin were found to be down-regulated. Poly(A) PCR cDNA analysis showed there was no correlation between the protein expression changes and mRNA levels. Western blot analysis also indicated no change in the levels of mortalin or leukotriene A4 hydrolase, indicating that post-translational events may modify protein content of the specific spots. Leukotriene B4 levels (product of leukotriene A4 hydrolase) were, however, reduced in cells exposed long term to Bcr-Abl activity. This study demonstrates the potential of proteomic analysis to define novel effects of oncogenes.

Animals↗
PubMed1991

Growth regulation of malignant clonogenic cells in acute myeloid leukemia.

Myeloid leukemic progenitor cells proliferate in vitro in response to a variety of humoral factors, the most prominent among these being granulocyte-macrophage colony-stimulating factor (GM-CSF). The mechanism by which GM-CSF transduces its proliferative signal in acute myeloid leukemia has been extensively investigated over the past year. It is now known that the GM-CSF belongs to a new family of hematopoietic growth factor binding proteins which are characterized by a relatively short intracytoplasmic domain that lacks a tyrosine kinase sequence. Nevertheless, studies performed using GM-CSF-dependent leukemic cell lines demonstrate the appearance of several new phosphotyrosine species after GM-CSF exposure, suggesting that receptor activation is directly or indirectly linked to tyrosine kinase stimulation. Apart from the basic biology of GM-CSF-induced signal transduction, the ability of this factor to enhance the S-phase fraction of myeloid leukemia blasts may have important therapeutic implications. Clinical trials are currently being conducted in an attempt to determine whether GM-CSF is able to overcome kinetic resistance of leukemic myeloblasts to cell cycle-specific agents such as cytarabine in the treatment of patients with acute myeloid leukemia.

Clone Cells↗
PubMed1998

Bone marrow transplantation for chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by an initial chronic phase of expanded clonal myelopoiesis followed by inevitable progression to accelerated phase and finally to fatal blast crisis. Although interferon therapy results in hematologic control of disease in most patients and major cytogenetic responses in 30% to 35%, resulting in better survival than with conventional therapy with hydroxyurea or busulfan, most patients have residual disease detectable by molecular methods. Allogeneic bone marrow transplantation may cure selected patients with CML and should be considered early in the course of disease. Newer approaches to therapy include autografting using mobilized peripheral blood stem cells. Selection and expansion of nonleukemic progenitors may improve outcome following autologous transplantation. Advances in understanding of mechanisms of action of antisense oligonucleotides, ribozymes, and tyrosine kinase inhibitors and the immunologic responses to CML cells are also likely to lead to novel approaches to therapy.

Bone Marrow Transplantation↗