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PubMed1987

Ph1-positive CML-derived myeloid-monocytoid precursor cell line producing substance(s) that stimulates normal CFU-C.

A new Ph1-chromosome positive cell line, KOPM-28. was established from a patient with chronic myelogenous leukemia (CML) in blast crisis. KOPM-28 cells were phenotypically immature: without azurophilic granules; negative for myeloperoxidase and positive for specific and nonspecific esterases. The nonspecific esterase reaction was intensified by TPA, and retinoic acid reinforced the specific esterase reaction without inducing morphological changes. KOPM-28 cells were not phagocytic. The cells expressed complement receptors, myeloid-monocytoid antigens, an Ia-like antigen and T4 antigen. CALLA, T-lymphocyte specific antigens, B-lymphocyte related antigen and platelet-megakaryocyte-megakaryoblast specific antigen were not detected. KOPM-28 cells formed colonies in semi-solid medium; this ability was augmented by GM-CSA. The addition of culture medium conditioned by KOPM-28 cells to normal bone marrow cells resulted in the increase of the CFU-C colonies. These findings indicate that KOPM-28 cells have features of myeloid and monocytoid precursor cells and that they are producing substance(s) which stimulates normal CFU-C.

Antigens, Surface↗

PubMed1990

Lineage non-specific down regulation of P210bcr/abl in the CML cell line, KU-812-F, during differentiation.

CML cell line, KU-812-F, originally established from a patient with Philadelphia-chromosome-positive chronic myelocytic leukemia has maintained the ability to differentiate into both granuloid (basophilic) and erythroid lineages. The expression of P210bcr/abl in KU-812-F cells during differentiation was studied by immunoblotting and immunoprecipitation. Immunoblotting with anti-phosphotyrosine sera revealed the down-regulation of P210bcr/abl in both granuloid and erythroid lineages. Immunoprecipitation with anti-abl antibodies of 35S-methionine-labelled cells revealed a reduced rate of synthesis of P210bcr/abl protein. Cytotoxic agents that caused growth inhibition of the cells did not alter the expression of P210bcr/abl. These results indicate that the down regulation of P210bcr/abl protein is a lineage non-specific event accompanied by differentiation.

Cell Differentiation↗

PubMed1995

Selective inhibitors of 5-lipoxygenase reduce CML blast cell proliferation and induce limited differentiation and apoptosis.

Inhibitors of the arachidonic acid metabolizing enzyme, 5-lipoxygenase, reduce the rate of proliferation of chronic myelogenous leukemia blast cells. The inhibitory agents studied were ETYA, A63162 and SC41661A. These reagents induced differentiation of cultured chronic myelogenous leukemia cells from blast to promyelocytic morphology. Promyelocytic cells then underwent apoptosis, which was identified by nuclear and cytoplasmic morphological features and by DNA laddering. Proliferation of monoblastoid U937 and myelomonocytic HL60 cell lines, known to contain 5-lipoxygenase and synthesize leukotrienes, was reduced by these inhibitors. U937 cells cultured with ETYA, A63162 or SC41661A for 48 h exhibited apoptosis as assessed by DNA laddering and morphology. Characteristic ultrastructural changes of apoptosis were seen at 120 h. MK886, an inhibitor of 5-lipoxygenase with a mechanism of action distinct from oxidation/reduction reagents, at 20-40 microM also inhibited CML and U937 cell proliferation and induced apoptosis, as shown by DNA laddering and ultrastructure.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1996

Detection of c-myc oncogene amplification in a CML blastic phase patient with double minute chromosomes.

Double minute chromosomes (dmin) are relatively rare in leukemias. Cytogenetic analysis of blood cells from a woman with blastic phase chronic myelogenous leukemia (BC-CML) showed numerous dmin chromosomes and complex abnormalities including a Philadelphia (ph(1))-chromosome. Oncogene amplification in hematopoietic malignancies is also rare. Using PCR, we retrospectively investigated the extent of c-myc gene amplification in DNA extracted from stored blood smears from the patient. To qualify the PCR products, the beta-globin gene was used as the internal reference gene and it was co-amplified with the c-myc gene. The extent of amplified c-myc was about 6.8-fold. This finding suggests that the c-myc gene was amplified in dmin and that the gene amplification contributes to the progression to acute leukemia or rapid growth of leukemic cells.

Base Sequence↗

PubMed1981

Chromosomal anomaly of 6q in chronic myelogenous leukemia (CML).

Anomalies of chromosome 6q, along with other chromosomal anomalies, are described in the bone marrow cells of two patients with chronic myelogenous leukemia (CML). One patient a 14-year-old male, developed the karyotype 46,XY,t(1;6)(p36;q15),del(3)(q25), del(17)(p11),? inv(17)(q12q24) during blastic crisis of his disease. The other patient, a 24-year-old male, had the karyotype 46,XY,del(6)(q13),5(9;22)(q34;q11) during the early phase of his disease and evolution of i(17q) in the karyotype late in the disease.

Adolescent↗

PubMed1982

A photometric study of the standard Philadelphia (Ph1) translocation of chronic myeloid leukemia (CML).

A newly developed form of high resolution microscope photometry has been employed in a study of the relationships between the chromosomes involved in the standard Philadelphia (Ph1) translocation of chronic myeloid leukemia (CML). The intention of the investigation was to provide quantitative data on the relative amount of material exchanged between the No. 9 and No. 22 chromosomes. A marked consistency in the amount of material lost from the Ph1 was observed, and the balanced nature of the standard Ph1 translocation was confirmed. The data are also in accordance with the concept of a reciprocal exchange between the No. 9 and No. 22 chromosomes.

Bone Marrow Cells↗

PubMed1984

Chromosome changes and splenectomy in Ph1-positive CML. II. Prognostic aspects in the blastic phase.

The effect of splenectomy during the blastic phase (BP) in Philadelphia (Ph1) positive chronic myeloid leukemia (CML) was correlated with the chromosome findings during that phase of the disease. Fifty-three patients were divided into six groups on the basis of the chromosome findings and splenectomy; i.e., nonsplenectomized and splenectomized patients with only a Ph1 clone (PP/S- and PP/S+); nonsplenectomized and splenectomized patients with a clone containing only a Ph1 and another clone with karyotypic changes in addition to the Ph1 (AP/S- and AP/S+), and nonsplenectomized and splenectomized patients with only abnormal clone(s) containing karyotypic abnormalities in addition to the Ph1 (AA/S- and AA/S+). The percentage of patients with a good therapeutic response in each group was higher in splenectomized than nonsplenectomized patients. The median survival after the onset of BP was 171 days (5.7 months) in PP/S-, 167 days (5.6 months) in PP/S+, 136 days (4.5 months) in AP/S-, 183 days (6.1 months) in AP/S+, 23 days (0.8 months) in AA/S-, and 155 (5.2 months) in AA/S+. Statistically, there was a significant difference only between AA/S- and the other groups. These findings may indicate that splenectomy during the blastic phase could contribute to an improved tolerance to chemotherapy in each group and prolong the survival after the onset of BP in AA patients.

Adolescent↗

PubMed1985

Cytogenetically distinct leukemic cell lines displaying in vitro specific proliferative and differentiation capacities may account for early disease relapse in the blast phase of CML.

The cytogenetic features and the proliferative and differentiation capabilities of blast cell fractions purified on a density gradient were studied in one patient with chronic myeloid leukemia (CML) in blast crisis, both at the emergence and at relapse of the disease. The results show that relapse was due to the appearance of a new leukemic cell line that was characterized by peculiar chromosomal, growth, and differentiation features, which seemingly accounted for early refractoriness to therapy and disease progression.

Adult↗

PubMed1985

Unusual Ph translocations in CML: four new cases.

Four variants of the Ph chromosome translocation in chronic myelogenous leukemia (CML) patients are described. Two had an unusual simple translocation involving chromosomes #7 and #17. In two cases, the translocation, aside from involving #9 and #22, involved a third chromosome, chromosome #6 and chromosome #11, respectively. Three cases showed also karyotypic evolution during the blastic phase of the disease: in two cases, a new reciprocal translocation was found that involved a chromosome #9 at band q34. The clinical and cytogenetic significance of these results is briefly discussed.

Adolescent↗

PubMed1985

Value of cytogenetic studies in prediction of acute phase CML.

Twenty-five patients with Ph CML who eventually developed a blast crisis were karyotyped at regular intervals in order to correlate the evolution of abnormal clones with clinical changes. Persistent new clones appeared in the chronic phase, prior to either transition or transformation, or in the acute phase (the latter, particularly, where transformation was slow). In many patients, chromosome changes accumulated within a single abnormal clone as the disease progressed. In others, particularly where the simple Ph cell line was slow to be supplanted, new clones appeared from the remaining Ph cells at the time of transformation, perhaps reflecting the inability of certain chromosome abnormalities to coexist. We suggest that the occurrence of additional chromosome abnormalities is not reliable evidence of acute transformation, but that the nature and subsequent behavior of abnormal clones may provide more valuable indications.

Adolescent↗

PubMed1985

Philadelphia chromosome (Ph) positive chronic myelocytic leukemia (CML): frequency of additional findings.

This article documents the cytogenetic findings in 79 patients with typical Ph-positive chronic myelocytic leukemia (CML). Direct preparations of bone marrow and/or peripheral blood of 46 males and 33 females were studied with different banding techniques. Seventy patients were studied during chronic phase. Three (4.3%) had unusual or complex translocations: t(6;22)(p21;q11), t(8;12;9;22)(p21;q21;q34;q11), and t(9;11;22)(q34;q13;q11). One (1.4%) had a +Ph, 1 (1.4%) had a +8, 1 (1.4%) had a del(3)(p13,p23), and 4 of 30 males (13.3%) showed loss of Y chromosome. Five of 8 cases studied during blast crisis had additional abnormalities. The +8 occurred in 4 cases, +10 and +19 each in 3 cases, +6, + 9q+, and +13 each in 2 cases, and +5, +11, +14, +21, +Ph, i(17q), dic(1;9), and structural abnormalities of chromosomes #1, #5, #12, and #13 each in 1 case. Two cases studied in blast crisis alone had complex translocations leading to the Ph. Because it cannot be ruled out that these translocations are secondary, they were not included in the calculation of the frequency of atypical translocations.

Adolescent↗

PubMed1995

Detection of M-bcr/abl fusion by fluorescence in situ hybridization (FISH) in a case of Ph negative CML.

A balanced reciprocal translocation, t(6;9)(p21;q34), was identified in a female patient diagnosed with chronic myeloid leukemia (CML). Both homologs of chromosome 22 were of normal length and morphology. Southern blotting revealed a bcr rearrangement with BglII and HindIII. Two signals for the abl probe were demonstrated by fluorescence in situ hybridization (FISH), one on the normal chromosome 9 and the second on a chromosome 22. Thus, molecular rearrangement of bcr resulted from insertion of an abl gene within the bcr region despite absence of a Ph chromosome.

Chromosomes, Human, Pair 6↗

PubMed1994

Trisomy 8 detection in Ph+ CML patients using conventional cytogenetic and interphase fluorescence in situ hybridization techniques.

We examined bone marrow (BM) cells from 6 Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) patients in advanced phase of the disease using conventional cytogenetic techniques and fluorescence in situ hybridization (FISH) for detection of an extra chromosome 8. All patients showed mosaicism for trisomy 8 as a secondary chromosome abnormality. For FISH, we used the D8Z5 probe specific for the centromeric region of chromosome 8 and analyzed 300 interphase nuclei and a variable number of mitoses for each patient. The percentages of metaphases carrying trisomy 8 were similar with both techniques, whereas the percentage of interphase nuclei showing three hybridization spots indicative of trisomy 8 was significantly lower than that in metaphases. This finding suggests that cells with a supernumerary chromosome 8 may have a cell cycle time shorter than that of disomic cells.

Aged↗

PubMed2006

Accumulation of gamma-globin mRNA and induction of irreversible erythroid differentiation after treatment of CML cell line K562 with new doxorubicin derivatives.

Human chronic myelogenous leukemia (CML) cell line K562 can be chemically induced to differentiate and express embryonic and fetal globin genes. In this study, the effects of doxorubicin (DOX), an inducer of K562 cell erythroid differentiation, with those of epidoxorubicin (EDOX) as well as newly synthesized derivatives of both drugs (DOXM, DOXH, and EDOXM) on cell growth and differentiation were compared. Our results revealed that DOX, EDOX and their derivatives caused irreversible differentiation of K562 cells into more mature hemoglobin-containing cells. This phenomenon was linked to time-dependent inhibition of cell proliferation. Considering the impact of the structure of newly synthesized anthracyclines on their cellular activity, our data clearly indicated that among tested anthracyclines DOXM, a morpholine derivative of DOX exerted the highest antiproliferative and differentiating activity. An increase of gamma-globin mRNA level caused both by high transcription rate and by mRNA stabilization, as well as an enhancement of expression but not activity of erythroid transcription factor GATA-1 were observed. Therefore, a high level of hemoglobin-containing cells in the presence of DOXM resulted from transcriptional and post-transcriptional events on gamma-globin gene regulation. The same morpholine modification introduced to EDOX did not cause, however, similar effects on cellular level. Characterization of new powerful inducers of erythroid differentiation may contribute to the development of novel compounds for pharmacological approach by differentiation therapy to leukemia or to beta-globin disorder, beta-thalassemia.

Antineoplastic Agents↗

PubMed2004

Differences and similarities in kinetics of BCR-ABL transcript levels in CML patients treated with imatinib mesylate for chronic or accelerated disease phase.

Kinetics of BCR-ABL transcript levels were determined in 19 patients with chronic myeloid leukemia (CML) treated with imatinib for chronic (CP) or accelerated phase (AP). Patients could be divided into three groups with: (1) a sharp and sustained decrease in BCR-ABL transcript level reaching 0.1-0.002% (only CP); (2) an early BCR-ABL overexpression up to 2500% (only AP); and (3) a stable trend with BCR-ABL values between 10 and 100% (CP, AP). In group 1, relapses were not developed within the follow-up; in group 2, patients progressed to blast crisis; in group 3, BCR-ABL overexpression appeared after 12 months in some patients and disease relapses were found 2-16 weeks later. It is summarized that BCR-ABL transcript kinetics clearly characterize responses to imatinib treatment and are highly predictive for disease progression.

Adult↗

PubMed2004

Comparison of M-FISH and conventional cytogenetic analysis in accelerated and acute phases of CML.

FISH and multicolor FISH (M-FISH) techniques have greatly enhanced the resolution of conventional cytogenetic analysis, thus enabling the identification of novel regions of rearrangement in hematological malignancies. We report on the analysis of cells from 24 chronic myelogenous leukemia (CML) patients, in either accelerated phase (14 cases) or blast crisis (10 cases) aimed at searching for previously unidentified additional abnormalities related to disease evolution. Indeed, in 6 of 24 cases (25%) M-FISH allowed a more precise description of chromosomal aberrations, the finding of cryptic rearrangements, characterization of markers, identification of additional material and a better interpretation of complex aberrations. However, new recurrent aberration did not emerge from M-FISH analysis.

Adult↗

PubMed2005

Structural analysis and expression profile of a novel gene on chromosome 5q23 encoding a Golgi-associated protein with six splice variants, and involved within the 5q deletion of a Ph(-) CML patient.

We have identified a novel gene, upstream of the cytokine gene cluster region in 5q23-31, residing within one of the most common deleted segments associated with MDS. The novel gene exhibits significant alternative splicing generating at least six splice variants encoding four putative proline-rich protein isoforms, one of which is Golgi-associated. The gene is ubiquitously expressed and conserved among species with the C. elegans homologue being the most interesting, since it resides within an operon with two other genes, phospholipase D and dishevelled, a member of the Wnt pathway, suggesting a functional association. In addition, the novel gene and other key regulatory genes of the region, such IL3, Ril, AF5q31 and TCF-1, were found to be deleted in an atypical CML case, thus underscoring the significance of this subregion in the leukemogenesis process.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Elderly patients with Ph+ chronic myelogenous leukemia (CML): results of imatinib mesylate treatment.

Thirty-five patients with Ph+ CML aged more than 60 years were treated with imatinib. Twenty-four patients (group A) were in late chronic phase (CP) and eleven patients (group B) were in accelerated/blastic phase (AP/BP). In group A, complete haematological response (CHR) was achieved by all patients; seventeen patients (70.8%) attained a complete cytogenetic response (CCR), one (4.1%) attained a partial CR, one (4.1%) a minor CR (Ph+ 70%) and five (21%) were resistant (Ph+ 100%), toxicity was mild: seven patients had a transient cytopenia, three a skin reaction, one a moderate oedema and one muscular pain. After a median follow-up of 15 months, 1 patient died in progression and 23 patients are alive (2 in BP and 21 in persisting response). In group B, one patient died after 3 months in aplastic phase from sepsis, three patients were resistant and seven patients (63.7%) achieved CHR; of these, four obtained CCR. After a median follow-up of 17 months, 4 patients have died from progressive disease, 6 are alive; 1 in AP and 5 in CHR (4 of them being in CCR). Present data indicate that imatinib is safe also in elderly with clinical results as good as in younger patients.

Age Factors↗