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PubMed1992

Detection of minimal residual disease by polymerase chain reaction of bcr/abl transcripts in chronic myelogenous leukaemia following allogeneic bone marrow transplantation.

The prognostic significance of detecting minimal residual disease by polymerase chain reaction (PCR) amplification of bcr/abl mRNA transcripts was investigated in 27 bone marrow samples from 20 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukaemia (CML) in complete cytogenetic remission following allogeneic bone marrow transplantation. Sixteen were transplanted in first chronic phase, two were in second chronic phase, one was in accelerated phase and one was in blast crisis. All 20 achieved complete cytogenetic remission post transplant and 15 patients had detectable bcr/abl mRNA by PCR from 2 to 22 months following the procedure. One of these patients had graft failure and one died from graft-versus-host-disease at 7 months. Of the remaining 13 PCR-positive patients, only one (8%) relapsed after 23 months; the other 12 were alive and still in remission after a median follow-up of 16+ months (ranging 5+ to 29+ months). Five patients were PCR negative; all are alive in complete clinical and cytogenetic remission at 10+, 11+, 19+, 25+ and 25+ months post transplant. In this study, detection of subclinical Ph1-positive cells by PCR was not associated with imminent clinical or cytogenetic relapse. Since late recurrence may potentially occur, long-term follow-up is required to definitely determine the prognostic value of the PCR assay.

Adult↗
PubMed1986

Comparison of morphologic features and mitotic rate to cytometrically determined DNA content of poorly differentiated lymphocytic lymphomas.

A direct correlation between the percentage of cells in S phase of the cell cycle and the clinical behavior of lymphocytic lymphomas of low, intermediate, and high grade malignancy has been described. The histopathologist has used the mitotic rate and other morphologic criteria such as size of cells and nuclear characteristics as predictors/indicators of the aggressiveness of a tumor. We compared the S phase values of 22 cases of poorly differentiated lymphocytic lymphoma (PDL) of the B cell type, using flow cytometric measurement of DNA content, to morphologic features and mitotic rate (MR). The 22 cases were divided into 3 histologic groups: nodular PDL composed of small, cleaved lymphocytes (11 cases); follicular mantle zone lymphoma and those of intermediate differentiation (6 cases); and "blastic" PDL (5 cases). In Group 1 there was excellent correlation of MR, percentage of cells in S phase, and proportion of large cells (transformed lymphocytes) per high power field (HPF). In Group 2, this correlation was not found between MR and percentage of cells in S phase in five of the six cases. The high S phase in this group did correlate with the large proportion of large cells found primarily in pseudofollicular proliferation centers and in remnants of true follicular centers. These cells may have a prolonged S phase and thus fewer mitoses were seen. In Group 3, although both MR and S phases were high, a direct correlation between them as noted in the Group 1 cases was not seen, but an excellent correlation of the high S phase and the number of blasts was present. The fact that three of the five patients in this group died rapidly (within less than 2 years of presentation) and the two survivors were experiencing rapid progression of disease, supports the concept that this group represents a clearly different, more aggressive subclass of PDL.

DNA↗
PubMed1976

Persisting production of out-of-cycle blasts during methotrexate therapy in acute leukaemia.

Kinetics of the blast populations in two cases of acute lymphoblastic leukaemia during treatment with methotrexate have been studied in vivo. Beside a striking cytocidal effect on blasts arrested in the S phase and a synchronization and a slowing of those in the G2 phase, the most important finding was the persistence of a flux of drug-affected cells from the proliferation of the non-proliferating compartment. Some of these non-proliferating cells were able to re-enter subsequently the mitotic cycle. This fact can explain why a cell-cycle-specific drug fails to eradicate completely acute leukaemic cells in man.

Adult↗
PubMed1983

[Different effects of cytostatics on cell kinetics of normal and leukemic human bone marrow in vitro].

The kinetics of the erythropoietic and of the granulocytopoietic pool of normal und leukemic human bone marrow cells were investigated in vitro under the influence of 23 cytostatic drugs. Clot cultures were evaluated up to 72 hours by differential and mitotic counting in smears stained according to Pappenheim. Based on mitotic index, caryological curve and percentage of proliferative cells different patterns of proliferation were observed: spindle poisons enhanced the mitotic index, all other investigated cytostatic drugs diminished it, but in a different degree the one of the erythroblasts, of the granuloblasts and of the leukemic blasts. The decrease of the percentage of proliferative precursors did not always correlate with the decrease of the mitotic index, because sometimes an ineffective granulocytopoiesis arised or leukemic blasts entered the Go-phase of the cell cycle. 1-asparaginase was the only drug which increased erythroblasts. Chloramphenicol was the only out of 18 drugs tested on leukemic bone marrow that decreased only the leukemic proliferation and had no influence on the normal one.

Acute Disease↗
PubMed2002

Microsatellite instability and cytogenetic survey in myeloid leukemias.

Microsatellites are short tandem repeat sequences dispersed throughout the genome. Their instability at multiple genetic loci may result from mismatch repair errors and it occurs in hereditary nonpolyposis colorectal cancer. This instability is also found in many sporadic cancers. In order to evaluate the importance of this process in myeloid leukemias, we studied five loci in different chromosomes of 43 patients, 22 with chronic myelocytic leukemia (CML) in the chronic phase, 7 with CML in blast crisis, and 14 with acute myeloid leukemia (AML), by comparing leukemic DNA extracted from bone marrow and constitutional DNA obtained from buccal epithelial cells. Only one of the 43 patients (2.1%), with relapsed AML, showed an alteration in the allele length at a single locus. Cytogenetic analysis was performed in order to improve the characterization of leukemic subtypes and to determine if specific chromosome aberrations were associated with the presence of microsatellite instability. Several chromosome aberrations were observed, most of them detected at diagnosis and during follow-up of the patients, according to current literature. These findings suggest that microsatellite instability is an infrequent genetic event in myeloid leukemias, adding support to the current view that the mechanisms of genomic instability in solid tumors differ from those observed in leukemias, where specific chromosome aberrations seem to play a major role.

Adolescent↗
PubMed2000

Leptin receptor and leukemia.

The receptor for leptin, the gene product of the obese gene, is expressed in hematopoietic stem cells. Leptin stimulates normal myeloid and erythroid development, and is secreted from bone marrow adipocytes, which occupy most of the marrow cavity in humans. Leptin might thus play an important role in the control of the expansion and differentiation of primitive hematopoietic cells through paracrine interaction in the bone marrow microenvironment. Leukemic cells of some patients with acute myeloblastic leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia (CML) also express the leptin receptor. In cases of CML, higher expression of leptin receptor is observed during blast crisis than in chronic phase. Leptin alone and in combination with other cytokines has stimulative effects on proliferation of leukemia cells as well as anti-apoptotic effects. These findings suggest the possibility that leptin plays roles in the pathophysiology of leukemia.

Carrier Proteins↗
PubMed2000

[Autologous bone marrow transplantation for patients with chronic myelogenous leukemia after in vitro purging of the graft with bcr/abl antisense oligodeoxynucleotides].

OBJECTIVE: To investigate the efficacy of autologous bone marrow transplantation (ABMT) for patients with chronic myelogenous leukemia (CML) after in vitro purging of the graft with bcr/abl antisense oligodeoxynucleotides (AS-ODN). METHODS: Five CML patients, 2 in chronic phase (CP), 1 in accelerated phase (AP) and 2 in blast crisis (BC), all confirmed the presence of b3a2 bcr/abl mRNA by RT-PCR (reverse transcriptase-polymerase chain reaction). Patients had received 2 courses of intensive chemotherapy for "in vivo purging" before bone marrow harvesting. The autologous bone marrow cells were concentrated by CS3000plus and then incubated with 18-mer phosphorothioate bcr/abl AS-ODN (40 - 60 microg/ml, for 48 - 60 h). Conditioning regimens were TBI + Cy (total body irradiation + cyclophosphamide) or MAC + CCNU. RESULTS: After intensive chemotherapy, ph(+) cells in bone marrow reduced to 34% (24% - 46%) and the numbers of bcr/abl mRNA (+) CFU-GM to 45.6% (33% - 58%). After bcr/abl AS-ODN in vitro purging, two patients were bcr/abl mRNA negative and three positive with the number of bcr/abl mRNA (+) CFU-GM markedly reduced. Delayed hematopoietic reconstitutions were observed in all patients after ABMT. During a more than 2 years follow-up period, three patients obtained major cytogenetic remission (MCR) and lasted for 9 - 12 months and the durations of CP after ABMT were longer than that before ABMT. One of this three in BC before ABMT being survived disease-freely for 37 months with bcr/abl mRNA (-) after ABMT. Another patient in BC had a short duration of MCR and relapsed at +7 months. One patient died from severe infection and bleeding at day +74 because of delayed reconstitution. CONCLUSION: ABMT with bcr/abl AS-ODN purged graft can result in quite long duration of MCR and prolonged CP in some patients with CML.

Adolescent↗
PubMed2003

A novel gene, MSI2, encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23).

The pathogenetic role of the P210 BCR/ABL1 fusion gene in the chronic phase of chronic myeloid leukemia (CML) has been well established.In contrast, the genetic mechanisms underlying the disease progression into the accelerated phase (AP) and the final blast crisis (BC) remain poorly understood. We have previously identified (A. Barbouti et al., Genes Chromosomes Cancer, 35: 127-137, 2002) two cryptic balanced translocations, t(7;17)(p15;q23) and t(7;17)(q32-34;q23), in CML AP/BC using multicolor fluorescence in situ hybridization. In this study, we show that a novel gene in 17q23, Musashi-2 (MSI2), encoding a putative RNA-binding protein, is rearranged in both cases and that a MSI2/HOXA9 fusion gene is formed in the case with the 7p15 breakpoint. The identified in-frame MSI2/HOXA9 fusion transcript retains both of the RNA recognition motif domains of MSI2, which is fused to the homeobox domain of HOXA9, and is likely to play an important role in the disease progression of CML.

Adult↗
PubMed2005

Haemopoietic growth factors in myelodysplastic syndromes: towards patient-oriented therapy?

Recombinant human erythropoietin (r-EPO) has been used in Myelodysplastic Syndrome (MDS) patients with anaemia since the early nineties. In low-risk MDS patients, other haemopoietic growth factors (HGFs) (granulocyte-colony stimulating factor, G-CSF, granulocyte-macrophage-colony stimulating factor, GM-CSF, and interleukin 3, IL-3) have been used to synergise the effects of r-EPO on erythroid growth and to increase neutrophil count in patients with severe neutropenia. In high-risk MDS, or in patients with post-MDS AML, myeloid HGFs have been used to push blasts into the S-phase, thus increasing their sensitivity to antiblastic drugs. Several trials have shown that r-EPO can increase haemoglobin levels and improve QoL in patients with anaemia associated to MDS. The selection of patients with a high probability of response to HGFs is based on the careful consideration of several clinical and biological parameters, i.e., among others, basal EPO and transfusional needs, disease duration, FAB or WHO subtypes, and IPSS score. Treatment of anaemic MDS patients with HGFs should become "patient oriented" and different types, schedules, and duration of treatment have to be designed according to the specific criteria which most likely predict, for each individual patient, the best chance of responding favourably to therapy.

Anemia↗
PubMed1991

[Prevalence and features of pre-B-cell acute lymphoblastic leukemia in Mexico: description of 9 patients].

A group of 9 patients with pre-B cell acute lymphoblastic leukaemia (pre-B ALL) was identified prospectively within 209 patients with ALL. This variant of leukaemia was defined by the presence of heavy mu-chains in the cytoplasm of the malignant cells, and no surface immunoglobulins. Four patients displayed the CD10 (CALLA) antigen, in addition to cytoplasmic mu chains. A G-0 acute leukaemia (no blast cells in S-phase) was identified in two cases. Response to treatment of the patients was poor: Only four achieved complete remission; median survival was 24 weeks and the 40-week disease free survival was 20%. These figures are significantly worse than those obtained in patients with early-pre-B (CD10+) ALL. We conclude that the prevalence of pre-B ALL is low in our experience (4.6% of all patients with ALL) and that a poor outcome of treatment was related to it.

Adult↗
PubMed1989

Cellular events during memory T-cell activation in vitro: the UCHL1 (180,000 MW) determinant is newly synthesized after mitosis.

After T-cell activation, a switch of leucocyte common antigen (LCA) expression occurs which is detected by the disappearance of CD45R and the appearance of UCHL1 positivity. Upon activation of CD45R+ T cells by phytohaemagglutinin (PHA), the IL-2 receptor (IL-2R) develops at 15 hr and blast cells enter the S phase at 20 hr, while remaining UCHL1-. At 40 hr, mitotic cells continue to express CD45R determinants, but weak UCHL1 reactivity is now detectable on 15-20% of these cells. By inhibiting the separation of daughter cells with cytochalasin B, it can be demonstrated that the UCHL1 antigen is newly synthesized in the Golgi apparatus before insertion into the membrane after the first mitosis. At 65 hr after activation, 80% of proliferating cells are UCHL1+. T cells undergo a similar development during allogeneic activation, and specific alloresponsive cells, tested in secondary mixed lymphocyte reaction (MLR), become greatly enriched among the proliferating UCHL1+ cells. Conversely, after a primary MLR, residual CD45R+ T cells are unresponsive to the original stimulus but can still proliferate in response to unrelated alloantigens. These results clarify both the time-course of the acquisition of UCHL1 antigen during the proliferative cycle of activated T cells, and indicate the shift of antigen responsive T-cell populations from the CD45R+ to the UCHL1+ pool.

Cells, Cultured↗
PubMed1986

t(14;14)(q11;q32) in biphenotypic blastic phase of chronic myeloid leukemia.

A blastic crisis of chronic myeloid leukemia without a detectable chronic phase is reported. At diagnosis, blast cells present t(9;22)(q34;q11),t(14;14)(q11;q32) translocations and early B cell phenotype (DR +, TdT +, B4 +, BA1 +, J5 +). At relapse, the malignant clone evolves to a biphenotypic expression, the initial markers remain unchanged, and two myeloid antigens (My 7, My 9) appear. The wide overlap in percentages of blast cells displaying lymphoid and myeloid markers shows that a single clone bears antigens of both lineages. Simultaneous occurrence of a t(14;14)(q11;q32) translocation, usually found in T cell malignancies, and of a B cell phenotype raises the question of the relationship between chromosomal changes and surface marker expression. The malignant cell is assumed to be a progenitor cell, already committed to lymphoid lineage and retaining the potential to switch to myeloid lineage.

Aged↗
PubMedDate not supplied

Lysis of fresh leukemic blasts by interferon-activated human natural killer cells.

In a comprehensive study of 30 leukemia patients, it was found that a measurable fraction of fresh leukemic blasts from 8 of 8 adult patients with chronic myelogenous leukemia (CML) in blast crisis and 10 of 11 pediatric patients with childhood acute lymphocytic leukemia (ALL) were efficiently lysed by human peripheral blood natural killer (NK) cells as measured in 4-hour chromium release assays. The observed lysis of these fresh, noncultured, neoplastic blasts was mediated by a population of interferon-augmentable, FcR-positive, non-adherent large granular lymphoid cells from normal donors, which were also able to kill the 'standard' NK target K562. It was of further interest that all 8 of the patients with blast crisis CML exhibited myeloid type morphology. Furthermore, neoplastic lymphoblasts from 9 of 10 patients with NK-susceptible childhood ALL lacked easily detectable B or T cell markers and were of 'null' cell type. In marked contrast to the lytic susceptibility of fresh leukemic blasts from patients with ALL and CML in blast crisis, fresh neoplastic granulocytes from 5 patients with chronic phase CML (2 of which eventually progressed to myeloid type blast crisis), as well as leukemic blasts from 8 patients with acute myeloid leukemias (AML, AMMoL, and AMoL) were resistant to lysis as mediated by human NK cells from normal donors. The clinical implications of these findings are discussed.

Adolescent↗
PubMed1981

Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia.

We performed a pilot study to test the effectiveness of allogeneic bone marrow transplantation in the treatment of chronic myelogenous leukemia. Five patients in the advanced stages of chronic myelogenous leukemia (four in blast crisis, one in accelerated phase) with abnormal chromosomes underwent matched-sibling allogeneic bone marrow transplantation after preparation with busulfan, vincristine, cyclophosphamide, and fractionated total body irradiation. Engraftment and conversion to normal chromosome patterns after transplantation occurred in all five patients. None of the patients reverted to an abnormal chromosome pattern of demonstrated clinical or hematologic evidence of recurrent disease during the course of this study; however, longest survival from transplant was 248 days. Allogeneic bone marrow transplantation can eradicate the abnormal clone even in far advanced chronic myelogenous leukemia and can provide normal hematopoiesis. We suggest that clinical complications of chemotherapeutic toxicity and infection were responsible for the short survival in this group of patients, and that these complications could be decreased by performing transplantation in the chronic phase or early accelerated phase of the disease.

Adult↗
PubMed1993

Bcr-abl mRNA expression in patients with chronic myeloproliferative disorders--absence of bcr-abl fused clone except chronic myelocytic leukemia.

Bcr-abl mRNA expression was studied in patients with chronic myeloproliferative disorders (CMPD) by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. A bcr-abl transcript was not found in any patient with polycythemia vera, essential thrombocythemia or primary myelofibrosis, suggesting that the bcr-abl rearranged clone is not present in CMPD other than chronic myelogenous leukemia (CML). In CML clinical and laboratory data were compared from three bcr-abl types: the bcr exon 2-abl exon 2 (B2-A2) type, bcr exon 3-abl exon 2 (B3-A2) type and the co-expression type. Age at diagnosis tended to be younger (p = 0.08) in the co-expression type, and the platelet count tended to be lower (p = 0.11) in the B2-A2 type. However, there was no difference in other data, including the duration of the chronic phase and the phenotype of blasts at blast crisis.

Adult↗
PubMed1995

Deficient cell cycle control in myeloid cells of patients with newly diagnosed chronic myeloid leukemia.

Cell cycle control subsequent to gamma irradiation or growth factor starvation has been studied in immative hematopoietic cells of 19 previously untreated chronic myeloid leukemia (CML) patients in chronic phase compared with 18 normal controls. CD34-positive cells were cultured for seven days in the presence of optimal concentrations of appropriate growth factors. At day 7 of culture both S-phase fraction and differentiation were identical in normal and leukemic cells. In normal cells the proportion of S-phase cells was reduced by irradiation with 500 rad from 40 +/- 3% to 16 +/- 2%. In contrast, in CML cells a reduction of S-phase cells from 35 +/- 2% to 25 +/- 3% was observed. Moreover, irradiated CML cells arrested at a smaller number of cells in G2. Similarly, a significantly higher proportion of CML cells remained in S phase after withdrawal of growth factors. Semiquantitative PCR of p21 (waf1/cip1) induction by gamma irradiation provided no evidence for a major functional deficiency of p53 response to irradiation in these cells. Our results demonstrate an abnormal cell cycle arrest in chronic-phase CML cells both after gamma irradiation and after growth factor removal. This observation might have important implications for understanding the pathogenesis of both hyperplasia of chronic phase and the development of blast crisis in CML. The molecular mechanisms underlying these abnormalities in bcr-abl-positive cells remain to be clarified.

Actins↗
PubMed2001

Sensitivity to the abl inhibitor STI571 in fresh leukaemic cells obtained from chronic myelogenous leukaemia patients in different stages of disease.

STI571 (CGP57148B) is an inhibitor of BCR/ABL, the cause of chronic myeloid leukaemia (CML). A difference exists between CML patients in chronic phase, in which responses to STI571are durable, and patients in blast crisis, who generally experience only transient responses. Leukaemic cells from six CML patients from whom samples could be obtained during chronic phase and at the time of blast crisis (BC) were compared for sensitivity to STI571, using an in vitro assay. BC samples showed a sensitivity similar to that obtained during chronic phase, suggesting that no substantial intrinsic resistance to STI571 was present in BC.

Adult↗
PubMed1994

[Molecular study on minute alterations of the p53 and the N-ras genes in hematologic malignancies].

Minute alterations of the p53 tumor suppressor gene and N-ras oncogene were investigated in 106 samples for the p53 gene and 23 samples for the N-ras gene obtained from patients with various types of hematologic malignancies using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct nucleotide sequencing. Mobility shifts suggesting sequence alteration were observed in 9 cases (8.5%) in exons 5 through 8 containing evolutionarily highly conserved regions of the p53 gene by PCR-SSCP; missense point mutations in 3 cases (1 acute myelogenous leukemia (AML), 1 chronic myelogenous leukemia (CML) in the accelerated phase, and 1 CML in the blast crisis), silent point mutation in 1 case (malignant lymphoma), and frame shift mutations due to insertions and deletions causing stop codons in 3 cases (1 AML, 1 CML in the chronic phase and 1 acute lymphoblastic leukemia (ALL)). p53 gene alterations did not always cluster within evolutionarily highly conserved regions, and there were various base change forms in cases with p53 point mutations. p53 mutations were detected in 2 cases out of 4 cases with 17 monosomy. There was no case with p53 gene alteration in myelodysplastic syndrome (MDS) cases. Mobility shifts suggesting sequence alteration were observed in 5 cases (22%) in exon 1 and 2 of the N-ras gene by PCR-SSCP. 3 cases (1 MDS, 1 MDS overt AML and 1 ALL) were detected to contain missense point mutations. However, simultaneous mutations in both the genes were detected in only 2 cases out of 23, thereby indicating infrequent occurrence of concomitant mutation of both the genes in hematologic malignancies. Alterations of the p53 and the N-ras genes are involved in the tumorigenesis, progression and prognosis of at least some cases of hematologic malignancies, in spite that they are relatively infrequent.

Base Sequence↗