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PubMed1998

[Genetic instability of microsatellites Mfd41 and DCC in the evolution of chronic myelogenous leukemia].

OBJECTIVE: To explore the relationship between the genetic instability of microsatellite and the evolution of chronic myelogenous leukemia(CML). METHODS: The loss of heterozygosity(LOH) and the microsatellite instability(MSI) of two polymorphic microsatellite markers, DCC and Mfd41, which located on chromosome 18q and 17p respectively, were assayed by standard PCR-silver staining analysis in bone marrow cells from 17 CML patients progressing from chronic phase to accelerated phase or blast crisis. RESULTS: LOH or MSI of the two microsatellites were demonstrated in 8/17 (47.5%) patients in accelerated/blastic phases. For DCC, genetic instability was revealed in 2 of 9 patients in accelerated phase and in 4 of 8 in blast crisis. For Mfd41, genetic instability was revealed in 1 of 9 patients in accelerated and in 1 of 8 in blast crisis. CONCLUSION: Genetic instability of DCC and Mfd41 may play a role in the evolution of CML.

Adolescent↗
PubMed1989

[Chronic myelogenous leukemia characterized by successive lymphoid and myelomonocytic blast crises].

We report a 25 year-old male of CML, who repeated lymphoid blast crises twice and finally experienced a myelomonocytic blast crisis. In the first and the second crises, after 2 years of chronic phase, the blasts were only weakly positive or negative for terminal deoxynucleotidyl transferase. Based on other morphological features of the blasts, however, lymphoid blast crisis was strongly suspected. Actually, he responded well to the vincristine and prednisolone therapy. In the third crisis, the blasts showed myelomonocytic features. He did not respond to the same regimen, and died of intracranial infiltration during daunorubicin and cytosine arabinoside therapy after one year from the first crisis. Chromosomal analysis showed the karyotypes of 46, XY, t(9:22) (q34:q11) in the chronic phase, 45, XY, -7, -9, +der(9) t(7;9) (q11;p11), t(9:22) (q34:q11) in the lymphoid blast crisis, and 46, XY, t(9:22) (q34:q11), t(11:17) (q23:q25) in the myelomonocytic blast crisis.

Adult↗
PubMed1999

Comparative analysis of G-banding, chromosome painting, locus-specific fluorescence in situ hybridization, and comparative genomic hybridization in chronic myeloid leukemia blast crisis.

The molecular basis for blast transformation of chronic myeloid leukemia (CML) remains poorly understood. Cytogenetic alterations associated with CML blast crisis have previously been extensively studied by conventional G-banding analysis. However the complexity of some chromosome abnormalities or poor chromosome morphology or both has exceeded the resolution of G-banding analysis in a significant proportion of CML cases, and complex chromosome rearrangements have remained unidentified. In this study, comparative genomic hybridization (CGH) was used to elucidate genome imbalances in chronic phase or blast crisis samples or both from 12 CML patients. CGH and G-banding results were compared, and discrepancies were further clarified by using multipaint chromosome analysis and locus-specific DNA probes. No imbalances were detected in the 4 early disease phase samples studied. Eleven blast crisis samples were analyzed by G-banding and CGH, and the commonest genomic abnormality detected was overrepresentation of the long arm of chromosome 8, which was detected in 5 patients. This overrepresentation was attributable to trisomy 8 in 4 patients, whereas amplification of the entire long arm of chromosome 8 was detected in 1 patient. The formation of isochromosomes of the long arm of chromosome 8 was observed as a mechanism for gene amplification in this patient. Additional material originating from chromosome 8 was also observed intercalated into three marker chromosomes in peripheral blood metaphase spreads from this patient. These markers may further define areas on chromosome 8 that harbor oncogenes implicated in transformation of chronic myeloid leukemia.

Adolescent↗
PubMed1988

Immunoglobulin and T-cell receptor gene rearrangement in blast crisis of chronic myelocytic leukemia.

Chronic myelocytic leukemia (CML) displays a wide repertoire in its terminal phase, with blast cells showing characteristics of myeloid, B-lymphoid, or T-lymphoid cells in some patients. Blast crisis (BC) cells from 14 patients were studied for immunoglobulin (Ig)- and T-cell-associated gene rearrangements. Five myeloid BC patients had no Ig- or T-cell-associated gene rearrangement. In contrast, all eight patients with pure lymphoid BC displayed C mu rearrangement and two also showed kappa-light chain rearrangement. One patient with mixed (lymphoid and erythroid) BC, however, showed neither Ig- nor T-cell-associated rearrangements. One patient displayed both Ig- (C mu) and T-cell-associated (T beta and T gamma) rearrangements. These cells expressed CD9, CD10, and CD24 surface antigens, but no T-cell antigens. Although most lymphoid blast crises appear to represent an early stage in B-cell differentiation, some cells have undergone apparently inappropriate gene rearrangements during differentiation. Such cells may have been immortalized while undergoing normally occurring nonproductive rearrangement or may, due to their malignant nature, display abnormal genotypic characteristics.

Antigens, Surface↗
PubMedDate not supplied

Differential display analysis of mRNAs in chronic myelogenous leukaemia.

Analysis of expressed mRNAs with differential display-polymerase chain reaction (DD-PCR) is a powerful tool for the characterization of genes involved in malignant pathways and might identify markers for different phases of chronic myelogenous leukaemia (CML). We examined the presence of BCR-ABL transcripts in 25 CML patients in either the chronic phase or blast crisis. We then analysed the expression of leukocytic RNA transcripts in CML phases. DD-PCR technique was used to examine CML cases with BCR-ABL in comparison with CML cases lacking detectable BCR-ABL transcripts. Our results support the use of differential display not only for characterization of the CML differentially expressed genes but also to locate patterns that can be implemented as valuable fingerprints for each phase of CML.

Adolescent↗
PubMed2003

[Study of adhesion-related molecule beta1-integrin and focal adhesion kinase in chronic myeloid leukemia].

OBJECTIVE: To study the changes in the expressions of beta1-integrin receptor (CD29) and focal adhesion kinase (FAK) during the deterioration of chronic myeloid leukemia (CML), thereby explore the potential mechanism of interferon (IFN)-alpha in the treatment of CML through testing the quantitative changes of FAK. METHODS: Bone marrow mononuclear cells were tested for CD34, CD29 and FAK monoclonal antibody by flow cytometry in CML patients of the chronic phase and blast crisis and in normal subjects. In the presence or absence of IFN-alpha, the bone marrow mononuclear cells from CML patients of chronic phase and normal subjects were cultured for 48 h to determine the content of FAK in the cells with Western blotting. RESULTS: CD 29 expression on the surface of CD34+ cells scarcely differ between normal subjects and CML patients of chronic-phase, but the intracellular content of FAK was lower in the latter. The expression of beta1-integrin receptor on the surface of hematopoietic cells in CML patients with blast crisis was significantly higher than that in chronic-phase CML patients, but the intracellular FAK in the former patients was lower. No difference of FAK content was observed in normal mononuclear cells before and after IFN-alpha treatment, while the treatment increased FAK content in the mononuclear cells in chronic phase CML patients. CONCLUSION: The changes in the expressions of beta1-integrin receptor and FAK may play important roles during CML deterioration, and IFN-alpha may function to repair the defect in the beta1-integrin receptor pathway by restoring the cellular content of FAK.

Adult↗
PubMed1993

Frequent p53 overexpression in therapy related myelodysplastic syndromes and acute myeloid leukemias: an immunohistochemical study of bone marrow biopsies.

p53 overexpression was studied immunohistochemically in paraffin-embedded bone marrow biopsies using a recently described technique for antigen retrieval based on microwave oven heating of paraffin sections. Using a monoclonal antibody (PAb1801) that reacts with human cellular p53, nuclear staining was detected in 7/11 (63%) therapy-related myelodysplastic syndromes and in 3/4 (75%) therapy-related acute myeloid leukemias. Conversely, staining for p53 was seen only in 9/40 (22%) cases of "primary" hematologic conditions (P < 0.007); these included myelodysplastic syndromes [#2], acute myeloid leukemia [#4], and chronic granulocytic leukemia in accelerated phase or blast crisis [#3]. Biopsies of normal controls and of chronic granulocytic leukemia in stable phase were consistently p53(-). Nine of the 10 karyotyped p53(+) acute myeloid leukemia/myelodysplastic syndrome cases showed complex cytogenetic findings with frequent involvement of chromosome 5 and/or 7. Only four of the 33 karyotyped p53(-) cases showed similar cytogenetic changes. Chromosome 17 involvement was present in four of 13 (31%) cytogenetically assessed p53+ cases, but in none of the p53(-). In univariate analysis, p53 expression in both MDS and AML was significantly associated with shorter survival. The frequent overexpression of p53 in therapy-related myelodysplastic syndromes, therapy-related acute myeloid leukemias and in accelerated phase/blast crisis, chronic granulocytic leukemia and its strong association with complex karyotypes suggests an important role of this gene in the pathogenesis of these leukemic conditions.

Acute Disease↗
PubMed2003

Cost-utility analysis of imatinib mesilate for the treatment of advanced stage chronic myeloid leukaemia.

Imatinib mesilate (Glivec), Novartis Pharmaceuticals) is a novel therapy for the treatment of chronic myeloid leukaemia (CML). We evaluated the cost-effectiveness of imatinib (600 mg daily) when used for the treatment of patients in advanced stages of CML (accelerated phase and blast crisis) against conventional therapies of combination chemotherapy (DAT) and palliative care in hospital or at home. A Markov model simulated the transitions of hypothetical patient cohorts and outcomes were modelled for 5 years from the start of treatment. Costs were estimated from the perspective of the UK National Health Service. Over 5 years, a patient in accelerated phase will, on average, accrue an additional 2.09 QALYs with imatinib compared to conventional therapies, while patients in blast crisis will accrue an additional 0.58 quality-adjusted life-years (QALYs) with imatinib compared to conventional therapies. The costs per additional QALY gained from treatment with imatinib compared with conventional therapies were pound 29344 (accelerated phase) and pound 42239 (blast crisis). The results were particularly sensitive to the price of imatinib, improvements in quality of life, and the duration of haematological responses. We conclude that treatment of CML with imatinib confers considerably greater survival and quality of life than conventional treatments but at a cost.

Antineoplastic Agents↗
PubMed2003

How to make sure your spirometry tests are of good quality.

Poorly performed spirometry greatly increases the risk of misinterpreting spirometry results. The most common cause of erroneous results is suboptimal patient coaching. Use exaggerated body language to demonstrate each of the 3 phases of the forced vital capacity (FVC) maneuver. The first phase of the maneuver (the maximally deep breath) is the most important and should receive the most emphasis. In the second phase (the blast) startle the patient to prompt maximum flow during the first second. In the third phase do not yell at the patient to keep blowing; instead, draw the patient's attention to the movement of the bell of the volume spirometer, the computer incentive display, or the audio tone of the flow-sensing spirometer, which shows that he or she is continuing to get some air out. Pay attention to the patient's body language as you coach him or her through the 3 phases. Facial expressions and body language are much more important than telling the patient what to do. Use the latest National Health and Nutrition Examination Survey (NHANES III) reference equations and the ratio of forced expiratory volume in the first second to forced expiratory volume in the first 6 seconds (FEV(1)/FEV(6)). Young, old, and sick patients can produce high-quality, reproducible pulmonary function test results. Grade pulmonary function test efforts with the scholastic grading system (A, B, C, D, and F). Implement a centralized spirometry quality assurance program. Test your spirometers daily. Be cautious in making corrections for body-temperature-and-pressure-saturated.

Humans↗
PubMed1998

Mutational analysis of N-RAS and GAP-related domain of the neurofibromatosis type 1 gene in chronic myelogenous leukemia.

RAS mutations can be detected in a variable number of patients with myeloproliferative disorders such as myelodysplastic syndromes and acute myeloid leukemia, but are rare events in chronic myelogenous leukemia in chronic phase. However, there is good evidence supporting the involvement of RAS signalling pathway in CML and this could be due to alterations in RAS activity regulatory proteins. The neurofibromatosis (NF1) gene down-regulates the RAS signal transduction pathway through the inhibitory function of its GAP-related domain (GRD) on RAS protein. The loss or alteration of neurofibromin (the NF1 protein) may produce a disfunction similar to point mutations in the RAS gene resulting in the permanent stimulation of the RAS signal transduction pathway. Mutations involving the GRD region of the NF1 gene (GRD-NF1) have been described in a variety of tumors such as colon carcinoma and astrocytoma. Germline mutations and deletions in the NF1 gene, as seen in neurofibromatosis type 1, are also associated with certain myeloid disorders. In the present work, we sought to identify mutations in the codons 12/13 and 61 of RAS gene and in the Lys-1423 codon of GRD-NF1, which are well known hot spots in these genes, in a group of 36 adults and ten children with chronic myelogenous leukemia in chronic phase and blast crisis. Using the PCR-SSCP and the allele-specific restriction assay (ASRA) techniques, we were not able to observe any RAS or NF1 detectable mutation. These findings suggest that RAS and GRD-NF1 mutations are not involved either in chronic phase or in the progression to blast crisis in chronic myelogenous leukemia in adults and children.

Adult↗
PubMed1994

Clinical importance of P-glycoprotein-related resistance in leukemia and myelodysplastic syndromes--first experience with their reversal.

P-glycoprotein (P-gp) expression in mononuclear bone marrow cells was analyzed in 119 patients, including 60 with chronic myelogenous leukemia (CML), 48 with myelodysplastic syndromes (MDS), and 11 with acute myelogenous leukemia (AML). For P-gp measurement an immunocytological method using monoclonal antibodies C219, 4E3, and MRK 16 and the reverse transcription-polymerase chain reaction technique were applied. According to our results obtained in healthy volunteers using the immunocytological method, the limit for P-gp overexpression was set at > or = 10% P-gp-positive mononuclear bone marrow cells and at > or = 30% P-gp-positive mononuclear peripheral blood cells. All 42 CML patients in chronic phase had normal P-gp expression. P-gp overexpression was demonstrated in four of six patients in accelerated myelogenous blast cell phase and in four of 12 CML-BC patients. Of eight CML patients in blast crisis (BC) with normal P-gp expression, partial remission was achieved in three and minor response in five after prednisone/vindesine therapy. All four of the 12 CML-BC patients with P-gp overexpression did not respond to this therapy. Normal P-gp expression was seen in 41 (85.4%) of 48 untreated MDS patients. While P-gp overexpression did not develop during therapy in any of the myelodysplastic syndrome patients treated with low-dose ara-C alone, four of eight treated with low-dose ara-C plus GM-CSF and four of 11 treated with low-dose ara-C and IL-3 developed P-gp overexpression after therapy. Furthermore, 11 AML patients at primary diagnosis, including five AML patients with P-gp overexpression, who were treated with idarubicin, vepesid, and cytarabine V (ara-C) showed a complete remission. Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months. Our results suggest that in CML patients in BC, P-gp expression influences outcome after therapy. Further more, studies in a larger series of patients are necessary to prove the efficacy and toxicity of idarubicin/vepesid and cytardbine--or dexniguldipine-containing--therapy in relation to P-gp expression of AML patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

Phenotypic and genotypic analysis of chronic myelogenous leukaemia with T lymphoblastic and megakaryoblastic mixed crisis.

A case of blast crisis in chronic myelogeneous leukaemia (CML) in which two distinct cell lineages were involved is presented. The phenotype of blasts in lymph nodes was T11 (CD2)+, Ia+, TdT+, suggesting T cell lineage. On the other hand, blasts in bone marrow and peripheral blood expressed platelet glycoprotein IIb/IIIa complex on their surface, suggesting megakaryocyte lineage. Cytogenetic analysis of lymph node and bone marrow cells revealed the abnormalities, inv(7) (p15q34) and t(1;3) (q23;q21), respectively, as well as the presence of the Ph1 chromosome in both cell types. Rearrangement of the T cell receptor beta-chain gene was detected in lymph node blasts, although blast cells in peripheral blood showed a germ line configuration. The involvement of T cell and megakaryocyte lineages in the blast crisis phase of CML was confirmed in our phenotypic and genotypic analysis, and the pathogenic association between blast crisis lineages and the additional chromosome abnormalities present is discussed.

Blast Crisis↗
PubMed2005

Chronic myeloid leukemia presenting with extramedullary disease as massive ascites responding to imatinib mesylate.

Patients with chronic myeloid leukemia (CML) can develop extramedullary involvement during the course of the illness. This usually occurs during the accelerated phase or blast crisis. We describe a patient who presented with massive ascites probably due to mesenteric/peritoneal infiltration during chronic phase CML. There was an excellent response to imatinib with a complete cytogenetic response and total disappearance of ascites.

Antineoplastic Agents↗
PubMed2005

A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation.

Altered mRNA translation is one of the effects exerted by the BCR/ABL oncoprotein in the blast crisis phase of chronic myelogenous leukemia (CML). Here, we report that in BCR/ABL+ cell lines and in patient-derived CML blast crisis mononuclear and CD34+ cells, p210(BCR/ABL) increases expression and activity of the transcriptional-inducer and translational-regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K or HNRPK) in a dose- and kinase-dependent manner through the activation of the MAPK(ERK1/2) pathway. Furthermore, HNRPK down-regulation and interference with HNRPK translation-but not transcription-regulatory activity impairs cytokine-independent proliferation, clonogenic potential, and in vivo leukemogenic activity of BCR/ABL-expressing myeloid 32Dcl3 and/or primary CD34+ CML-BC patient cells. Mechanistically, we demonstrate that decreased internal ribosome entry site (IRES)-dependent Myc mRNA translation accounts for the phenotypic changes induced by inhibition of the BCR/ABL-ERK-dependent HNRPK translation-regulatory function. Accordingly, MYC protein but not mRNA levels are increased in the CD34+ fraction of patients with CML in accelerated and blastic phase but not in chronic phase CML patients and in the CD34+ fraction of marrow cells from healthy donors. Thus, BCR/ABL-dependent enhancement of HNRPK translation-regulation is important for BCR/ABL leukemogenesis and, perhaps, it might contribute to blast crisis transformation.

Antigens, CD34↗
PubMed1981

Chromosome abnormalities in Down's syndrome patients with acute leukemia.

Chromosome and cytologic studies were performed on three Down's syndrome (DS) patients with acute nonlymphocytic leukemia (ANLL). All three patients had an aneuploid clone in their leukemic cells: 50, XX, +6, +19, +21, +22, +8, XX, +21, and 47,XY, +8, - 21 +dic(21;21)(p13;p11). Every patient appeared to have acute undifferentiated leukemia when the blast cells were examined with Wright-Giemsa stain; cytochemistry studies, however, showed that the leukemic blasts were in an early stage of myeloid differentiation. The two patients with +8 had a preleukemic phase; the blast cells of the patient with an extra no. 19 and no.22 could not be differentiated morphologically from those of the two patients with an extra no. 8. Our findings and a review of data on 40 other patients suggest that most DS children with ANLL have hyperdiploidy, which is usually related to gains of C, F, and /or G chromosomes, and that the abnormalities of +8 and of +19, +22 in DS children may be associated with acute leukemia (AL) in an early stage of myeloid differentiation.

Acid Phosphatase↗
PubMed1996

Increasing methylation of the calcitonin gene during disease progression in sequential samples from CML patients.

In chronic myeloid leukaemia (CML), disease progression from the initial chronic phase to the acute phase or blast crisis has previously been shown to be correlated with progressive increases in hyper-methylation of the calcitonin gene, located at chromosome 11p15. However, sequential studies of individual patients were not performed in these investigations. We have analysed 44 samples from nine patients with typical Philadelphia chromosome positive CML throughout their disease progression to determine the methylation state of the calcitonin gene at these time points. Densitometry was used to quantitate the ratio of the normal 2.0 kb Hpa II fragments, indicating normal methylation status of the gene, compared to the intensity of the abnormal, hyper-methylated, 2.6-3.1 kb Hpa II fragments. We found a gradual increase in the ratio of methylated:unmethylated calcitonin gene during chronic phase with a dramatic rise at blast crisis. Further, the ratio of the abnormal hypermethylated 3.1 kb fragments to the methylated 2.6 kb fragment resulted in the identification of a clonal expansion of abnormally methylated cells. This expansion of cells with hypermethylation of the calcitonin gene during chronic phase was shown to coincide with the presence of a mutation in the p53 gene. The data presented in this study would suggest that an increased methylation status of the calcitonin gene during disease progression may indicate the expansion of abnormal blast cell populations and subsequent progression to blast crisis.

Blast Crisis↗
PubMed1993

Methylation of the major breakpoint cluster region (M-bcr) in Philadelphia-positive CML.

It has previously been shown that a cluster of HpaII sites with the potential to be methylated exist around exon b3 of the M-bcr region involved in the formation of the Philadelphia chromosome in chronic myeloid leukemia (CML). The degree of hypermethylation of these sites can be directly correlated with the percentage of immature cells, whilst progressive hypomethylation occurs during the maturation of the granulocyte lineage. We have examined samples obtained from CML patients at diagnosis, during chronic phase, and blast crisis to examine the degree of methylation of this region in the non-rearranged BCR gene and the rearranged BCR-ABL gene. A low degree of methylation of the non-rearranged gene, similar to that observed in normal individuals, was observed in diagnosis and chronic phase samples. Increased methylation was observed during blast crisis indicative of the presence of immature cells in the samples. In contrast, a significantly lower degree of methylation was observed in the rearranged BCR-ABL gene at the onset of blast crisis. Division of the samples into those patients who had lost exon b3 during the formation of the BCR/ABL gene and those that had retained exon b3 produced differing patterns of methylation during disease progression. The former group, who also expressed a b2-a2 mRNA, showed an increase in methylation of the non-rearranged BCR gene prior to and during blast crisis, with a inverse decrease in the methylation of the BCR/ABL gene. Those patients who had retained exon b3, and expressed a b3-a2 mRNA, showed no change in the extent of methylation of the BCR/ABL gene but did exhibit an increase in methylation of the BCR gene during blast crisis. The consequence of the differing degree of methylation during disease progression could affect, to some extent, the specificity of protein binding or RNA expression.

Chromosomes, Human, Pair 22↗
PubMed1996

Blastic transformation of p53-deficient bone marrow cells by p210bcr/abl tyrosine kinase.

Blastic transformation of chronic myelogenous leukemia (CML) is characterized by the presence of nonrandom, secondary genetic abnormalities in the majority of Philadelphia1 clones, and loss of p53 tumor suppressor gene function is a consistent finding in 25-30% of CML blast crisis patients. To test whether the functional loss of p53 plays a direct role in the transition of chronic phase to blast crisis, bone marrow cells from p53+/+ or p53-/- mice were infected with a retrovirus carrying either the wild-type BCR/ABL or the inactive kinase-deficient mutant, and were assessed for colony-forming ability. Infection of p53-/- marrow cells with wild-type BCR/ABL, but not with the kinase-deficient mutant, enhanced formation of hematopoietic colonies and induced growth factor independence at high frequency, as compared with p53+/+ marrow cells. These effects were suppressed when p53-/- marrow cells were coinfected with BCR/ ABL and wild-type p53. p53-deficient BCR/ABL-infected marrow cells had a proliferative advantage, as reflected by an increase in the fraction of S+G2 phase cells and a decrease in the number of apoptotic cells. Immunophenotyping and morphological analysis revealed that BCR/ABL-positive p53-/- cells were much less differentiated than their BCR/ABL-positive p53+/+ counterparts. Injection of immunodeficient mice with BCR/ABL-positive p53-/- cells produced a transplantable, highly aggressive, poorly differentiated acute myelogenous leukemia. In marked contrast, the disease process in mice injected with BCR/ABL-positive p53+/+ marrow cells was characterized by cell infiltrates with a more differentiated phenotype and was significantly retarded, as indicated by a much longer survival of leukemic mice. Together, these findings directly demonstrate that loss of p53 function plays an important role in blast transformation in CML.

Animals↗