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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expansion of the Philadelphia (Ph) chromosome positive clone in chronic myeloid leukemia (CML) may depend on its capacity to suppress the proliferation of Ph-negative stem cells, but this proliferative advantage might, in certain circumstances, be reversible. Various lines of evidence suggest that Ph-negative cells, albeit in a suppressed state, must still be present. As recently suggested, the expansion of 'putative' normal Ph-negative hemopoietic stem cells might have, in certain circumstances, a proliferative advantage over the Ph clone in CML. This suggests that the treatment of CML with intensive chemotherapy might allow the collection of Ph-negative hemopoietic cells in the early phase of recovery. Eight patients with acute phase chronic myelogenous leukemia (AP-CML) were treated with idarubicin, intermediate dose cytarabine and etoposide. During recovery from bone marrow aplasia, when the white blood cell count reached 0.3-1 x 10(-9), blood cells were collected with 2-5 (median 3) consecutive leukapheresis. In 5/8 patients, these peripheral cells were Ph-negative at the cytogenetic analysis. Moreover, in one case the polymerase chain reaction analysis performed to detect the presence of minimal residual disease in the cells collected by leukapheresis was negative, further confirming that this approach may induce a very high degree of suppression of the Ph-positive clones. After complete recovery, these five patients were subsequently treated with high-dose etoposide, cyclophosphamide and total body radiation (10 Gy, single dose) followed by reinfusion of Ph-negative peripheral blood stem cells. All these patients received cyclosporine A post-autotransplant in an attempt to induce acute graft-versus-host-disease. Three of 5 patients remain in clinical and cytogenetic remission 5-15 months post-transplant. It is concluded that Ph-negative peripheral blood stem cells can be recovered from patients with AP-CML and used successfully to restore Ph-negative hemopoiesis after high dose therapy.
Leukemia 1991 Jun
PMID:Therapy of acute phase chronic myelogenous leukemia with intensive chemotherapy, blood cell autotransplant and cyclosporine A. 167 80

Monoclonal antibody (MAb) AP64 is a mouse IgM MAb raised against human acute non-lymphocytic leukemia (ANLL) cells. It has been shown to bind to a wide variety of cell lines and is capable of initiating complement (C) dependent cytotoxicity. Other studies indicated that MAb AP64 can effect long term cure in a leukemia minimal residual disease model. By using various techniques we have determined the identity of a protein which is bound by this MAb. Immunofluorescent studies have shown that MAb AP64 stains the nuclei of fixed cells as well as metaphase chromosomes, indicating that this MAb binds to a component of chromatin. Biochemical characterization revealed that MAb AP64 western blots a 31 and 32 kilodalton doublet from NP-40 extracts from both rat and human leukemia cells. The mobility of this doublet is identical under reducing and non-reducing conditions. Further studies have shown that the bands detected by western blot analysis using MAb AP64 as a probe have a similar migration to those of bovine histone H1. Also, 1 nanogram of bovine histone H1 can be detected by MAb AP64 when spotted onto nitrocellulose. These data demonstrate that MAb AP64 binds to a conserved epitope present on molecules coded for by the histone H1 gene family.
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PMID:A cytotoxic monoclonal anti-leukemia antibody binds to histone H1. 170 57

A detailed analysis of normal myeloid differentiation was performed using mutlidimensional flow cytometry. Based on two light scattering and three color immunofluorescence signals, the normal maturation pathways of both the monocyte and neutrophil lineages could be elucidated. Gradual changes of light scattering properties and cell surface antigen expression defined the pathways of each of the lineages. The consistency of the location of these lineage specific pathways found in normal individuals provided the basis for the discrimination between normal and leukemic cells in acute myeloid leukemia (ANLL). The position of leukemic cells in patients with ANLL in a five-dimensional space was compared with the position of the maturation tracks in normal individuals. The expression of normal antigens on leukemic cells provided the tools to: (1) distinguish normal from clonal populations of leukemic cells in all 15 patients; (2) detect a lineage predominance, either monocytic or neutrophilic, in all 15 patients; (3) detect maturation heterogeneity in all 15 patients. Although maturation pathways of the monocytic and the neutrophilic lineages were analogous to the normal patterns they were distinct in several ways. The expression of normal antigens on leukemic cells may provide the tools to: (1) obtain a new frame-work for classification of leukemia based on the ability to quantify the aberrant antigen expression and to define a 'distance from normal' based on the characteristics studied (the maturation heterogeneity of the leukemic cells also can be correlated with the clinical outcome of the patients); (2) detect minimal residual disease using the difference in locations of the leukemic cells in the multidimensional space from the normal maturation pathways (3) monitor relapse and changes in phenotypes which may accompany chemotherapy, suggesting the appearance of variant or new clones.
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PMID:Myeloid cell differentiation in normal bone marrow and acute myeloid leukemia assessed by multi-dimensional flow cytometry. 170 34

Immunotherapy with recombinant human interleukin-2 (IL-2) and allogeneic spleen cells has led to significant antitumor effects in B-cell leukemia- (BCL1) bearing mice following transplantation with T-lymphocyte-depleted allogeneic bone marrow cells. Graft versus leukemia (GVL) effects were studied in a model mimicking minimal residual disease following bone marrow transplantation (BMT). Lethally irradiated (BALB/c x C57BL/6)F1 recipients were reconstituted with 20 x 10(6) T-lymphocyte-depleted C57BL/6 bone marrow cells mixed with 10(4) to 10(6) BCL1 cells followed by administration of sequential increments of allogeneic C57BL/6 spleen cells; 10(6) cells on Day +1, 10(7) cells on Day +5, and 5 x 10(7) cells on Day +9, with or without concomitant IL-2 treatment (intraperitoneal injections of 20,000 U twice daily for 3 days) together with each spleen cell administration. All mice receiving 10(4)-10(6) BCL1 cells developed marked splenomegaly by Day +21 and all adoptive recipients of 10(5) spleen cells obtained from these mice developed leukemia within 21-36 days. Treatment of mice which received 10(4) BCL1 cells by either three courses of low dose IL-2 or three increments of allogeneic spleen cells alone and certainly by a combination of both resulted in normalization of splenomegaly on Day +21, but only adoptive recipients of 10(5) spleen cells obtained from mice treated by both allogeneic spleen cells and IL-2 (10/10) or allogeneic spleen cells alone (8/10) were disease free (greater than 100 days). Mice inoculated with 10(5) BCL1 cells developed mild splenomegaly on Day +21 after IL2 treatment alone, but showed no clinical evidence of disease following administration of allogeneic spleen cells or both allogeneic spleen cells and IL-2. Following adoptive transfer of 10(5) spleen cells obtained from each treated group no leukemia (greater than 100 days) was evident in recipients of spleen cells obtained from mice treated with both allogeneic spleen cells and IL-2 (10/10) whereas a partial effect was observed in mice treated by allogeneic spleen cells only (4/10). Mice inoculated with a high dose of BCL1 cells (10(6] showed some delay in onset of splenomegaly, but no curative antileukemic effects could be observed even following a synergistic combination of IL-2 and allogeneic spleen cells. Our data suggest that immunocompetent allogeneic lymphocytes may play an important role against leukemic relapse and thus cell therapy may be used therapeutically to treat minimal residual disease after BMT even following initial reconstitution with T-cell-depleted bone marrow cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Use of recombinant human interleukin-2 in conjunction with bone marrow transplantation as a model for control of minimal residual disease in malignant hematological disorders: I. Treatment of murine leukemia in conjunction with allogeneic bone marrow transplantation and IL-2-activated cell-mediated immunotherapy. 173 11

Diagnosis of leukemia and lymphoma has been made by morphological, cytochemical, and immunophenotypical methods. Recently molecular biological approaches have been introduced to clarify the cellular lineage of the tumor cells and to demonstrate the monoclonality. Southern blot analysis using immunoglobulin (Ig) and T cell receptor (TcR) genes revealed the presence of monoclonal components in some cases of angioimmunoblastic lymphadenopathy (AILD), in which demonstration of monoclonality was difficult by conventional methods. In preB-ALL, many cases had rearranged IgH and TcR genes simultaneously. These "dual genotype" cases were found to be of accidental involvement of TcR gene in the process of making effective IgH gene rearrangements by the precise analysis of rearranged IgH gene structures. The rearranged TcR gene which was detected in initial lymphoblastic lymphoma cells, was observed in relapsed blasts after lineage conversion to myeloid leukemia, which indicates the same clonal origin. Diagnosis and detection of minimal residual disease by the polymerase chain reaction (PCR) are now recognized as sensitive methods. PCR using oligonucleotides common to each VH and JH gene detects the rearranged IgH gene sensitively. PCR using primers located on the translocation boundary, such as bcr and abl in CML, is very useful in the diagnosis and pursuit of the disease course. PCR study also can be applied to the detection of alteration of some particular genes such as tumor suppressor genes.
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PMID:[Molecular diagnosis of leukemia and lymphoma]. 176 82

In chronic myelogenous leukemia (CML), amplification of a segment of bcr-abl messenger RNA (mRNA) by polymerase chain reaction (PCR) can be used to detect minimal residual disease after bone marrow transplantation (BMT). Previous studies have shown that this sensitive technique can often detect small numbers of leukemia cells in patients who are otherwise in complete remission. Nevertheless, the clinical significance of PCR positivity remains unclear because the majority of patients with PCR-detectable bcr-abl mRNA can remain disease-free for prolonged periods after allogeneic BMT. In the present studies, we applied PCR to detect bcr-abl-positive cells in 100 serial blood or BM samples from 24 patients with CML who underwent CD6 T-cell-depleted allogeneic BMT. After BMT, bcr-abl mRNA could be detected in 20 patients (83.3%) during complete cytogenetic or clinical remission. Patients in whom PCR positivity was sustained over time had a higher probability of CML relapse than patients in whom PCR was intermittently negative (P = .0095, log rank test). PCR detection of bcr-abl transcript between 2 and 10 weeks post-BMT also was associated with a high probability of subsequent relapse (P = .023, log rank test). In eight selected patients, we used a titration assay of the PCR-amplified product to estimate the number of residual tumor cells in each clinical sample post-BMT. PCR results in four patients showed a continuing increase in the number of tumor cells from early posttransplant until either cytogenetic or clinical relapse could be detected by conventional methods 1 to 2 years later. In contrast, PCR detected either no leukemia cells or relatively low and stable numbers of residual tumor cells throughout the follow-up period in four patients who remained in clinical remission. These results show that detection of the bcr-abl transcript by PCR after allogeneic BMT in patients with CML has important prognostic value. Estimation of the number of tumor cells in serial analyses can also be used to detect proliferation of the residual leukemic population. Sensitive detection of minimal residual disease can be used to assess the effectiveness of the transplant preparative regimen and to direct and evaluate further therapy post-BMT, before the development of overt relapse.
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PMID:Clinical significance of bcr-abl gene rearrangement detected by polymerase chain reaction after allogeneic bone marrow transplantation in chronic myelogenous leukemia. 182 68

T-cell receptor (TCR) delta gene rearrangements are observed in more than 80% of acute lymphoblastic leukemia (ALL) patients. Moreover, a preferential usage of specific genetic elements has been shown in different ALL subtypes: V delta 1 DJ delta 1 rearrangements predominate in T-ALL, while most B-precursor ALLs show a recombination of V delta 2 to D delta 3. Recently we have proposed a strategy for the detection of minimal residual disease (MRD) based on the isolation of clonospecific probes following the in vitro amplification of V delta 1 DJ delta 1 junctions by polymerase chain reaction (PCR) and now have adapted this method to the preparation of specific V delta 2 D delta 3 fragments. In the present study, clonospecific probes were generated from 11 T-ALL and 16 cALL patients (21 children, 6 adults). The sensitivity of these 27 probes in detecting residual leukemia cells varied between 10(-4) to 10(-6) as determined by semiquantitative evaluation of dilution experiments. PCR analysis of 55 bone marrow (BM) and peripheral blood (PB) samples obtained from the 27 patients during complete clinical remission showed the following results: (1) Evidence for MRD was obtained in the BM of all patients (eight of eight) investigated 2 to 6 months after remission induction and also in 6 of 11 cases on maintenance therapy 7 to 19 months after diagnosis. (2) In contrast, all patients but one (10 of 11) analyzed 6 to 41 months after the termination of treatment lacked apparent evidence for leukemia DNA; the exception was a girl exhibiting 10(-4) to 10(-5) residual cells in her PB 5.5 years after diagnosis. (3) Longitudinal analysis in nine patients disclosed marked individual differences in the intervals between achievement of clinical remission and complete eradication of the leukemia cell clone. (4) Differences in the duration of MRD were not associated with distinct clinical-hematologic features. (5) Detection of residual disease by PCR proceeded clinical relapse in two cases.
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PMID:Use of polymerase chain reactions to monitor minimal residual disease in acute lymphoblastic leukemia patients. 182 78

The polymerase chain reaction (PCR) is a novel technique for the in vitro amplification of specific short DNA fragments, which permits a selective and up to 10(7) fold enrichment of the target sequence. The method is increasingly being used for the molecular genetic analysis of hereditary, infectious and neoplastic disorders. The use of PCR for the detection of minimal residual disease in particular types of leukaemia or lymphoma, such as chronic myelogenous leukaemia expressing specific BCR/ABL-RNA and follicular non-Hodgkin lymphoma with the chromosomal translocation t(14;18) are reviewed. In acute lymphoblastic leukaemia clone-specific sequences from rearranged antigen receptor genes may be molecular markers suitable for amplification. Although PCR holds great promise for "molecular" staging and follow-up, several technical problems have to be kept in mind, and the clinical relevance of PCR-based evidence of minimal residual disease in haematological malignancies requires further investigation.
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PMID:The polymerase chain reaction: a new tool for the detection of minimal residual disease in haematological malignancies. 182 49

To detect more precisely the minimal residual disease in acute lymphoblastic leukemia (ALL), two-color flow cytometric analysis for the detection of cell-surface antigen (CD10; CALLA) and nuclear terminal deoxynucleotidyl transferase (TdT) was performed in the six patients with CALLA-positive ALL coexpressing TdT. In all patients, the leukemic blasts coexpressed Ia (HLA-DR), CD9, CD19, CD20, CD24, and CD10. Five of six patients achieved complete remission, but one has so far relapsed. No leukemic blasts (CD10+, TdT+) were detected at the time of complete remission. During maintenance chemotherapy, leukemic blasts coexpressed C10 and TdT were found 2.32% in the patient's peripheral blood by two-color analysis, whereas no obvious leukemic cells were recognized morphologically. The patient relapsed leukemia with the same phenotype 4 weeks after the examination. On the basis of our findings, we suggest that two-color flow cytometric analysis with the use of these antibodies is quite valuable to detect the minimal residual leukemic cells in a patient with ALL. The reduction of leukemic cells below the threshold of detection of methods currently available appears to be necessary to achieve a cure in ALL. Hence accurate diagnosis of ALLs with monoclonal antibodies (MAbs) should contribute substantially to the development of an effective form of therapy for their cure.
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PMID:Detection of minimal residual disease in acute lymphoblastic leukemia by flow cytometry with monoclonal antibodies. 183 4

Rearrangements, junctional regions and expression of T-cell receptor (TcR)-gamma and TcR-delta genes were analyzed in thirteen TcR-gamma delta + T-cell acute lymphoblastic leukemias (T-ALL). All TcR-gamma genes were rearranged except for one deleted allele and one allele in germline configuration. The expressed TcR-gamma protein chains showed a preference for V gamma l (11/13), J gamma 2.3 (7/13) and C gamma 2 (8/13). Furthermore, the TcR-gamma combinatorial repertoire appears to be even more limited by the fact that particular V gamma genes are preferentially used in TcR-gamma 1 or TcR-gamma 2 derived receptors, i.e. in disulfide-linked or non-disulfide-linked TcR-gamma delta receptors. The combinatorial repertoire of the expressed TcR-delta genes was homogeneous, as all thirteen T-ALL expressed V delta 1-D delta-J delta 1-C delta protein chains. In contrast to the limited combinatorial repertoire of the TcR-gamma and TcR-delta genes, the junctional diversity of both TcR genes was extensive due to insertion of N-region, P-region, and D delta gene nucleotides in addition to deletion of nucleotides by trimming. Using polymerase chain reaction (PCR)-mediated amplification and subsequent direct sequencing, we determined the junctional region sequences of all TcR-gamma and TcR-delta rearrangements. Sequence analysis showed that in the TcR-gamma junctional regions insertion varied from 0 to 25 nucleotides (average 8.0) and deletion from 1 to 27 nucleotides (average 8.7). In TcR-delta junctional regions, nucleotide insertion varied from 5 to 47 nucleotides (average 25.5) and deletion from 0 to 29 nucleotides (average 6.2) per junctional region. In general, the N-region nucleotides were the most prominent element in the junctional regions, i.e. 97% of the TcR-gamma and 55% of the TcR-delta junctional regions. D delta genes contributed significantly (40%) to the TcR-delta junctional diversity, whereas P-regions were hardly found in both TcR genes. Altogether, the junctional regions of TcR-delta genes were far more diverse than the junctional regions of TcR-gamma genes. With respect to the new methods of detecting minimal residual disease (MRD) in lymphoid malignancies utilizing PCR-mediated amplification of the junctional regions of TcR genes, our data indicate that this MRD-PCR analysis will generally be more sensitive if TcR-delta instead of TcR-gamma junctional-region-specific probes are used.
Leukemia 1991 Dec
PMID:Extensive junctional diversity of gamma delta T-cell receptors expressed by T-cell acute lymphoblastic leukemias: implications for the detection of minimal residual disease. 153 34


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