T F Zipf

Baylor College of Medicine, Houston, Texas, United States

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Publications (42)354.12 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously reported that children with B-precursor acute lymphoblastic leukemia (ALL) who remained in remission after successfully completing therapy had leukemia cells detectable by polymerase chain reaction (PCR) (N Engl J Med 1997;336(5):317-23). These patients were treated by an institutional protocol (P89-04) that lacked the post-remission intensification features of the contemporary Berlin-Frankfurt-Münster (BFM) based ALL protocols. In this report, we compared residual leukemia levels for patients on the P89-04 (n=15) and BFM-based Children's Cancer Group (CCG) studies (n=23) and for patients stratified according to risk group. Our goal was to establish which risk factors correlated with level of residual disease. Patients enrolled on the CCG protocols had lower levels of residual disease after completion of therapy than the P89-04 patients (P<0.019). Patients with high-risk disease also had lower levels of residual disease than patients with low risk disease (P<0.0001). Three-way analysis including time off treatment, risk group determined by features at presentation, and treatment protocol showed that risk group was the only significant independent variable (P<0.001).
    Leukemia Research 09/2003; 27(8):743-50. DOI:10.1016/S0145-2126(02)00324-7 · 2.35 Impact Factor
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    ABSTRACT: In a patient with precursor B-cell acute lymphoblastic leukemia (ALL) associated with eosinophilia that completely responded to induction chemotherapy, we assayed serial remission cerebrospinal fluid and bone marrow specimens for minimal residual disease using a quantitative polymerase chain reaction assay to assess for clone-specific immunoglobulin heavy-chain gene cluster (IGH) gene rearrangement. Cerebrospinal fluid eosinophilia and minimal residual disease were detected on day 406, preceding the morphologic diagnosis of central nervous system relapse on day 578. By day 841, the bone marrow had 35% blasts. Despite aggressive therapy, including unrelated umbilical cord blood transplantation, the patient developed testicular and bone marrow relapses and died of disease. We conclude that increasing levels of minimal residual disease in cerebrospinal fluid can predict recurrence of ALL prior to clinical and morphologic relapse. Furthermore, we demonstrate a novel translocation in this tumor, the t(5;9)(q31;p24), that possibly led to fusion of the interleukin-3 (IL3) (5q31) and JAK2 (9p24) genes and may explain the concomitant appearance of eosinophilia and ALL.
    Archives of pathology & laboratory medicine 06/2003; 127(5):601-5. DOI:10.1043/0003-9985(2003)127<0601:MMOCFC>2.0.CO;2 · 2.84 Impact Factor
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    ABSTRACT: Relapse is the major obstacle to cure for children with acute lymphoblastic leukaemia (ALL) after allogeneic bone marrow transplant (BMT). Development of salvage therapy for post-transplant relapse could be expedited by understanding the post-transplant behaviour of microscopically undetectable leukaemia and the ability to predict impending relapse. We have used a quantitative polymerase chain reaction method (sensitivity of 5.0 x 10-6) to measure residual leukaemia before the conditioning regimen, and at five time-points after transplantation. In total, 18 patients with ALL transplanted in first or second remission were studied for 1 year: For the first year post BMT, 12 remained in remission, four had haematological relapses, one had a cutaneous relapse, and one died of severe graft-versus-host disease. The post-engraftment levels of the leukaemia-specific immunoglobulin heavy (IgH) chain gene rearrangement for patients with haematological relapses were significantly different from those who remained in remission. The levels for the patients who remained in remission decreased with time, although there were occasional increases consistent with the known standard deviation of the measurement assay. In contrast, all clinical relapses were preceded by a rapid increase in levels. Both the rate of this increase and its timing were variable. These results suggest that residual leukaemia measurements can be used to direct post-transplant interventions and measure their effects.
    British Journal of Haematology 03/2003; 120(4):711-5. DOI:10.1046/j.1365-2141.2003.04135.x · 4.71 Impact Factor
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    ABSTRACT: In this prospective cohort study, minocycline-ethylenediaminetetraacetate (M-EDTA) was used as a lock solution in indwelling ports inserted in 14 children with cancer. No port infections, thrombotic events, or other adverse events were observed, compared with 10 port infections that occurred in 48 control patients whose ports were flushed with heparin. M-EDTA is a promising lock solution in long-term catheters.
    Clinical Infectious Diseases 02/2003; 36(1):116-9. DOI:10.1086/344952 · 8.89 Impact Factor
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    ABSTRACT: Complete remission of B-precursor acute lymphoblastic leukemia (ALL) has traditionally been defined as the near absence of lymphoblasts in a light-microscopical examination of stained bone marrow smears, but a patient in remission may still harbor up to 10(10) leukemia cells. We investigated whether there is a relation between the outcome of treatment and submicroscopic evidence of residual disease. We conducted a prospective study of patients during a first clinical remission using a quantitative polymerase-chain-reaction (PCR) assay capable of detecting 1 viable leukemia cell among 200,000 normal marrow mononuclear cells and a clonogenic blast-colony assay. Bone marrow specimens from 24 children were sequentially evaluated during a five-year period, and the results were compared with the clinical outcome. Seven patients relapsed and 17 remained in remission 2 to 35 months after the completion of treatment. The levels of residual leukemia-cell DNA in the two groups were significantly different (P<0.001; 95 percent confidence interval for the difference in the mean log-transformed ratio of leukemia-cell DNA to normal bone marrow-cell DNA, 0.38 to 1.28). Autoregression analyses identified trends for individual patients that were associated with relapse. Despite continued remission in 17 patients, evidence of residual leukemia was detected by PCR in 15 and by both PCR and blast-colony assays in 7. Molecular signs of residual leukemia can persist up to 35 months after the cessation of chemotherapy in children with ALL in remission. This suggests that eradication of all leukemia cells may not be a prerequisite for cure.
    New England Journal of Medicine 01/1997; 336(5):317-23. DOI:10.1056/NEJM199701303360501 · 55.87 Impact Factor
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    ABSTRACT: Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) is a malignant disorder characterized by a poor prognosis. In recent years hematopoietic growth factors have been used to recruit myeloid leukemia blasts into the proliferative phase of the cell cycle and as supportive agents, both with cytotoxic regimens and in the setting of bone marrow transplantation. This approach prompted us to investigate whether myeloid growth factors have a role in Ph1 positive ALL. To do this, we utilized two newly established Ph1-positive cell lines, Z-119 and Z-181. Both lines have L2 morphology, ultrastructural characteristics of lymphoblasts and typical B-lineage surface markers identical to those observed in the two Ph1-positive ALL patients from whom they were derived. In addition, a single rearranged immunoglobulin heavy-chain gene (JH) band was found in both cell lines by Southern blot analysis, confirming B-cell clonality. Cytogenetic analysis of the two lines revealed t(9;22). Polymerase chain reaction (PCR) amplified cDNA from both Z-119 and Z-181 cells revealed an e1--a2 BCR-ABL junction, and p190BCR-ABL protein was detected in them by the immune complex kinase assay. Both cell lines produce interleukin (IL)-1 beta, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), but neither IL-1 beta, G-CSF, their corresponding antibodies and inhibitory molecules, nor GM-CSF, affected the cell lines' growth. However, GM-CSF neutralizing antibodies inhibited Z-181 but not Z-119 colony formation in a dose-dependent fashion by up to 77% and addition of GM-SCF reversed this inhibitory effect. Receptor studies with radiolabeled GM-CSF demonstrated specific binding to Z-181 but not to Z-119 cells, and Scatchard analysis revealed that Z-181 cells express high-affinity GM-CSF receptors. Furthermore, PCR analysis showed that Z-181 but not Z-119 bears the transcript for the GM-CSF receptor. Finally, studies using PH1-positive ALL patients' marrow cells revealed similar data. In 3 of 8 samples we detected significant concentrations of GM-CSF (7.5-13 pg/2 x 10(7) cells) and in 2 of 3 cases GM-CSF significantly stimulated Ph1-positive ALL colony proliferation. These data suggest that Ph1-positive ALL cells may produce GM-CSF, express GM-CSF receptors and thus show a proliferative response to this cytokine.
    Journal of Cellular Physiology 03/1996; 166(3):618-30. DOI:10.1002/(SICI)1097-4652(199603)166:3<618::AID-JCP17>3.0.CO;2-2 · 3.84 Impact Factor
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    ABSTRACT: The polymerase chain reaction (PCR) has been applied to detect occult leukemia cells in children with acute lymphoblastic leukemia who are otherwise considered in complete remission by traditional morphological examination of bone marrow specimens. To determine whether PCR provides unique prognostic information of use for the clinical investigator, we reviewed the 20 clinical studies published to date. From this review, it is evident that discrepancies exist for the detection of residual disease for patients who remain in complete remission and for those who relapse. However, because of the fundamentally different approaches used to apply the PCR method to each of these studies, an entirely different interpretation can be reached when critical technical factors are considered. The combined data from the various studies suggest that a consistent pattern for residual disease disappearance over many months exists for patients who remain in extended complete remission and a pattern of residual disease persistence and reappearance preceding clinical findings exists for the majority of those who ultimately relapse in the bone marrow.
    Leukemia and Lymphoma 02/1996; 20(3-4):181-97. DOI:10.3109/10428199609051607 · 2.89 Impact Factor
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    ABSTRACT: The PCR technique appears to be the most sensitive method for detecting residual disease in ALL and can be applied to a high percentage of cases by amplifying sequences of the antigen-receptor genes. The PCR studies to date suggest that this sensitive technique can detect residual disease in virtually all patients during the first year of treatment. The residual disease becomes undetectable in the majority of patients by the end of treatment; however, a subset of patients remain PCR positive at a time when therapy is electively discontinued. The development of a highly accurate quantitative PCR technique may allow the possibility of distinguishing the patterns of residual disease for patients who will be cured by treatment from those who relapse. If such a pattern can be discerned, then an immediate benefit for PCR monitoring will be that clinicians will have the opportunity to test whether treating patients at the time of 'molecular relapse' will help to improve the cure rate for this disease. The PCR studies of remission marrows at the end of treatment raise a number of questions about the biology of disease persistence in patients who remain in extended 'remission.' A commitment to obtaining and analyzing bone marrow specimens in patients who have completed therapy is necessary to discern whether novel strategies, such as immunomodulatory manipulations, are needed to control or eradicated residual disease in patients who have completed planned chemotherapy. Thus, the long-term benefit of residual disease monitoring by PCR may be a better understanding of the biology and definition of 'cure' in ALL.
    Cancer treatment and research 02/1996; 84:149-66. DOI:10.1007/978-1-4613-1261-1_8
  • W M Roberts · Z Estrov · T F Zipf
    Blood 09/1995; 86(3):1237-9. · 10.45 Impact Factor
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    ABSTRACT: The polymerase chain reaction (PCR) has been applied to detect occult leukemia (ALL) cells in patients with acute lymphoblastic leukemia who are otherwise considered in complete remission by traditional morphological examination of bone marrow specimens. The combined data from the clinical studies published to date suggest that a consistent pattern for residual disease disappearance over many months exists for patients who remain in complete remission for an extended period of time. Conversely, a pattern of residual disease persistence and reappearance preceding clinical findings exists for the majority of patients who ultimately relapse. The ability to detect residual ALL disease near the end of chemotherapy or after the completion of treatment in some patients who otherwise are deemed likely to be cured of their malignancy raises the possibility that mechanisms other than leukemia cell cytotoxicity are influencing the outcome for this disease.
    Cytokines and molecular therapy 04/1995; 1(1):65-9.
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    ABSTRACT: The detection of residual leukemia cells in the bone marrow of patients during morphologic remission has been greatly facilitated by use of the polymerase chain reaction (PCR) to amplify leukemia-specific sequences. While the current PCR strategies for estimating the amount of residual leukemia claim a detection sensitivity of one leukemia cell amongst 10(5) or 10(6) normal cells, a rigorous assessment of the relative error associated with these techniques has not been presented. We have developed a method of estimating the amount of residual leukemia in remission marrows that is analogous to the limiting dilution assays used to determine the frequency of immunocompetent cells in a responder cell population. Using this method we measured the fraction of all-or-none (i.e. positive or negative) reactions of the PCR amplification of the leukemia-specific IgH gene rearrangement in replicate samples of serial dilutions of DNA obtained from diagnostic bone marrow specimens from 15 children with B-precursor acute lymphoblastic leukemia (ALL). A sigmoid curve representing the fraction of positive PCR reactions at a given dilution of leukemia DNA was found to be the best fit to the data. The narrowness of the log-linear region of this curve prevents the direct application of the analysis methodology that has previously been described for limiting dilution assays. However, the residual leukemia burden during morphological remission in these 15 patients and in two additional patients who experienced relapse could be estimated by the described dilution analysis method using the best-fit equation. Furthermore, the data generated for diagnostic, remission and relapse marrow samples exhibited a small interspecimen variation. The results suggest that this method can reliably estimate residual leukemia over a range of five orders of magnitude. Although the PCR reaction appears to be one of the most sensitive methods for detecting residual leukemia, all techniques based on this procedure, including our own, must exhibit limitations inherent to the amplification process. Our estimates or relative error suggest that a realistic limit for the PCR estimation of residual leukemia lies in the range of one leukemia cell per 10(5) normal cells. The suggested method is rapid, technically simple and relatively inexpensive. Furthermore, the principles that it is based upon can be applied to any PCR-based strategy.
    Leukemia 03/1995; 9(2):321-8. · 10.43 Impact Factor
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    ABSTRACT: Macrophage inflammatory protein-alpha (MIP-1 alpha), an 8-kDa peptide produced by stimulated macrophages, has been recently sequenced and cloned. In addition to its inflammatory effects, MIP-1 alpha inhibits proliferation of immature hematopoietic progenitors both in vitro and in vivo. Because the gene coding for MIP-1 alpha is expressed in peripheral blood cells obtained from patients with acute myelogenous leukemia (AML), we sought to evaluate the effect of MIP-1 alpha on AML precursors. We studied bone marrow samples from 21 AML patients using both the AML blast colony assay and the delta suspension culture assay. We found that recombinant human (rh) MIP-1 alpha significantly inhibits early and mature AML progenitors with sample-to-sample variability, by up to 79% at concentrations ranging from 40 to 1600 ng/ml. These results were obtained in the presence of fetal calf serum either alone or with granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or interleukin-3. In contrast, rhMIP-1 alpha (400 ng/ml) did not significantly affect normal colony-forming unit granulocyte-macrophage (CFU-GM), or burst-forming unit-erythroid (BFU-E) proliferation. These data prompted us to delineate the inhibitory mechanism of MIP-1 alpha. Consequently, we used the thymidine suicide technique to measure DNA synthesis in AML progenitors and the enzyme-linked immunosorbent assay to quantify intracellular levels of interleukin-1 beta in AML blasts following incubation with MIP-1 alpha. We found that whereas MIP-1 alpha prevented AML progenitors from entering the proliferative phase of the cell cycle, it had no effect on interleukin-1 beta levels. Taken together, our data suggest that MIP-1 alpha may have clinical benefits in therapy for AML and should be considered for evaluation in a clinical setting.
    Leukemia 06/1994; 8(5):798-805. · 10.43 Impact Factor
  • The Lancet 05/1994; 343(8901):858-9. DOI:10.1016/S0140-6736(94)92062-1 · 45.22 Impact Factor
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    ABSTRACT: No effective therapy is available for the majority of the 30-40% of children with acute lymphoblastic leukemia (ALL) who relapse. Since the morphologically undetectable, or occult, leukemia cells that persist during remission originate from the clone present at diagnosis, may also have both the capability to sustain the disease and to give rise to relapse, we are evaluating a method of identifying them. We have combined, for the first time, an ALL blast colony assay (BCA) and the polymerase chain reaction (PCR) to isolate residual leukemia cells in remission bone marrow aspirate specimens from eight patients with B-precursor ALL during early continuation therapy. We found colony-forming leukemia cells with in vitro self-renewal capability that survived chemotherapy for 15 months after diagnosis in all sequential specimens from these patients. To verify the leukemic nature of these cells their DNA was amplified by PCR and the product directly sequenced. In every case, the VHDJH sequence observed at diagnosis was found. None of the patients relapsed during this early phase of their treatment, consistent with the observation that patients with B-precursor ALL experience recurrence late in their course. Since it is possible that some of these persistent leukemia cells belong to the leukemia progenitor cell population that sustains the disease, the study of them could provide the means to determine the mechanisms of relapse.
    Leukemia 02/1994; 8(1):46-52. · 10.43 Impact Factor
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    ABSTRACT: We previously reported (Zwelling et al., Cancer Res50: 7116–7122, 1990) that etoposide induced DNA cleavage and mRNA coding for topoisomerase II are reduced in HL-60 cells induced to differentiate by phorbol ester. Reduction of etoposide-induced cleavage and topoisomerase II message did not occur in the derived cell line 1E3 (which is resistant to phorbol-induced differentiation), implying that topoisomerase II activity may be related to the state of cell differentiation. We have extended these studies using a new phorbol sensitive/resistant cell pair, S (sensitive) and PET (phorbol ester tolerant). Phorbol ester exposure not only reduced etoposide-induced DNA cleavage and topoisomerase II mRNA in S cells but also decreased the amount of immunoreactive topoisomerase II enzyme in whole S cells. However, immunoreactive topoisomerase II extracted from the nuclei of phorbol-treated S cells was not reduced compared with that from the nuclei of untreated S cells. This suggests that topoisomerase II contained in nuclear extracts is not always representative of the total cellular enzyme. Dramatic decreases in the amount, activity, or gene expression of topoisomerase II were not observed after phorbol treatment of the resistant PET cells; this is consistent with the potential involvement of topoisomerase II in monocytoid differentiation. Levels of topoisomerase I enzyme and mRNA fell in both S and PET cells after phorbol treatment; therefore, the genes for topoisomerases I and II did not appear to be regulated coordinately.
    Biochemical Pharmacology 02/1994; 47(2-47):387-396. DOI:10.1016/0006-2952(94)90030-2 · 5.01 Impact Factor
  • A Ferrajoli · T F Zipf · M Talpaz · E A Felix · Z Estrov
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    ABSTRACT: We investigated the effect of interleukin-4 (IL-4) on human hematopoietic progenitors using low-density bone marrow cells from 29 hematologically normal donors. We found that IL-4 could either inhibit or stimulate cell growth, depending upon the other constituents of the culture medium. At concentrations ranging from 0.1 to 10.0 micrograms/ml, it significantly inhibited colony-forming units granulocyte-macrophage (CFU-GM) in the presence of either fetal calf serum alone, erythropoietin, leukocyte-conditioned medium prepared with phytohemagglutinin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), or stem cell factor (SCF), in a dose-dependent fashion. In contrast, IL-4 stimulated CFU-GM colony multiplication in the presence of granulocyte colony-stimulating factor (G-CSF). Similar but less significant inhibitory effects were exerted by IL-4 on burst-forming units-erythroid (BFU-E). The growth-suppressive effect of IL-4 was partially reversed by IL-1 beta, and to a lesser extent by IL-6. When tested by enzyme-linked immunosorbent assay (ELISA), IL-4 suppressed cellular IL-1 beta production, and, similar to IL-4, anti-IL-1 beta-neutralizing antibodies inhibited CFU-GM colony growth, suggesting that the inhibition of endogenous IL-1 beta is a factor in regulating the IL-4 effect. Furthermore, in the absence of exogenous growth factors, IL-4 inhibited CFU-GM colony growth when anti-G-CSF neutralizing antibodies were also present. Therefore, we tested the effect of IL-4 on G-CSF receptors and found that 6- or 24-h incubation of low-density marrow cells with 1.0 microgram/ml IL-4 resulted in up-regulation of G-CSF receptors. Taken together, these results suggest that IL-4 possesses a dual modulatory role in the hematopoietic system via interaction with various cytokines.
    Annals of Hematology 01/1994; 67(6):277-84. DOI:10.1007/BF01696347 · 2.63 Impact Factor
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    ABSTRACT: To investigate the functional activity of interleukin 4 (IL-4) on human marrow stroma formation, normal bone marrow (BM) samples were cultured in "Dexter-type" long-term cultures in the presence and absence of IL-4. IL-4 (0.001 to 1.0 micrograms/ml) added at the initiation of culture and once weekly when the cultures were fed effaced the culture architecture. In four-week old confluent cultures smooth muscle-like and endothelial-like cells were rare, the fibronectin network and cobblestone areas were absent, and a preponderance of monocyte-macrophages characterized the adherent layer. Exposure to IL-4 reduced the numbers of CD34+ cells, colony-forming unit granulocyte-macrophage (GFU-GM) cells and burst-forming unit-erythroid (BFU-E) cells in the adherent layer, and increased their numbers in the nonadherent layer. In five of eight IL-4-containing cultures the concentrations of macrophage colony-stimulating factor (M-CSF) were increased and in two of eight IL-4-treated cultures the concentrations of tumor necrosis factor-alpha (TNF-alpha) were significantly elevated as compared to those in control cultures, whereas there were no consistent differences in the levels of either IL-6 or transforming growth factor-beta (TGF-beta). IL-1 beta and granulocyte-macrophage CSF (GM-CSF) were not detected in any culture. These data suggest that IL-4 suppresses stroma formation and alters its structure and cellular composition.
    Stem Cells 01/1994; 12(6):638-49. DOI:10.1002/stem.5530120611 · 6.52 Impact Factor
  • Zeev Estrov · Gian Guldo Re · T F Zipf
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    ABSTRACT: Despite significant improvement in the therapy for acute lymphoid leukemia (ALL) of childhood, approximately 30% of patients relapse. Unfortunately, since no successful treatment for recurrent disease has been developed, the majority of these patients die. Recently, we presented evidence consistent with the presence of a limited program of differentiation in B-precursor ALL that is reminiscent of normal B-cell development. We found that ALL cell populations consist of both a subpopulation of progenitors with the immunophenotype of normal B-cell precursors that has self-renewal capability and a second subpopulation with a more mature early B-cell immunophenotype that is without self-renewal capability but can proliferate to a limited extent. In our recent studies we were able to grow the progenitor cells in the ALL blast colony assay and establish their leukemic origin using the polymerase chain reaction. Our results suggest that these progenitors are the cells that sustain the disease. We hypothesize that these cells may remain quiescent, for a time, and either eventually die or regain proliferative capability and cause relapse. Further studies aimed both at detecting residual ALL and determining changes in their biology may provide an understanding of the mechanisms of relapse in this disease.
    Leukemia and Lymphoma 10/1993; 11(1-2):1-7. DOI:10.3109/10428199309054724 · 2.89 Impact Factor
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    ABSTRACT: The molecular hallmark of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) is the expression of 1 of 2 alternate forms of the aberrant BCR-ABL protein-p210BCR-ABL or p190BCR-ABL. The presence of BCR-ABL message provides a target for analyzing the lineage derivation of this disease. We, therefore, studied myeloid and erythroid progenitor involvement in Philadelphia chromosome-positive ALL. Bone marrow low-density cells from Philadelphia chromosome-positive ALL patients (5 with the p190BCR-ABL and 2 with the p210BCR-ABL anomaly) were cultured in the mixed colony culture assay. cDNA from individually plucked colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies was then analyzed using the hybridization protection assay in conjunction with the polymerase chain reaction to detect BCR-ABL molecular aberrations. Colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies from 1 of 5 p190BCR-ABL-positive patients and 1 of 2 p210BCR-ABL-positive patients expressed BCR-ABL transcripts, whereas colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid colonies from the other patients did not. Our study suggests that the origin of both p190BCR-ABL- and p210BCR-ABL-positive ALL is heterogenous with involvement of either a pluripotent precursor or a lymphoid lineage-committed hematopoietic progenitor.
    Cancer Research 08/1993; 53(14):3289-93. · 9.33 Impact Factor
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    ABSTRACT: Because human lymphotoxin (LT) was originally isolated from a lymphoblastoid cell line, we investigated the role of this molecule in three newly established Epstein-Barr virus (EBV)-infected human B cell lines. These lines were derived from acute lymphoblastic leukemia (Z-6), myelodysplastic syndrome (Z-43), and acute myelogenous leukemia (Z-55) patients who had a prior EBV infection. Each lymphoblastoid cell line had a karyotype that was different from that of the original parent leukemic cells, and all expressed B cell, but not T cell or myeloid surface markers. In all three lines, rearranged immunoglobulin heavy chain joining region (JH) bands were found, and the presence of EBV DNA was confirmed by Southern blotting. Z-6, Z-43, and Z-55 cell lines constitutively produced 192, 48, and 78 U/ml LT, respectively, as assessed by a cytotoxicity assay and antibody neutralization. Levels of tumor necrosis factor (TNF) were undetectable. Scatchard analysis revealed that all the cell lines expressed high-affinity TNF/LT receptors with receptor densities of 4197, 1258, and 1209 sites/cell on Z-6, Z-43, and Z-55, respectively. Furthermore, labeled TNF binding could be reversed by both unlabeled TNF, as well as by LT. Studies with p60 and p80 receptor-specific antibodies revealed that the three lines expressed primarily the p80 form of the TNF receptor. When studied in a clonogenic assay, exogenous LT stimulated proliferation of all three cell lines in a dose-dependent fashion at concentrations ranging from 25 to 500 U/ml. Similar results were obtained with [3H]TdR incorporation. Monoclonal anti-LT neutralizing antibodies at concentrations of 25-500 U/ml inhibited cellular multiplication in a dose-dependent manner. It is interesting that in spite of a common receptor, TNF (1,000 U/ml) had no direct effect on Z-55 cell growth, whereas it partially reversed the stimulatory effect of exogenous LT. In addition, TNF inhibited Z-6 and Z-43 cell proliferation, and its suppressive effect was reversed by exogenous LT. Both p80 and p60 forms of soluble TNF receptors suppressed the lymphoblastoid cell line proliferation and their inhibitory effect was partially reversed by LT. Our data suggest that (a) LT is an autocrine growth factor for EBV-transformed lymphoblastoid B cell lines; and (b) anti-LT antibodies, soluble TNF/LT receptors, and TNF itself can suppress the growth of lymphoblastoid cells, probably by modulating or competing with LT.(ABSTRACT TRUNCATED AT 400 WORDS)
    Journal of Experimental Medicine 04/1993; 177(3):763-74. · 12.52 Impact Factor

Publication Stats

1k Citations
354.12 Total Impact Points


  • 2003
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1991–1997
    • University of Texas MD Anderson Cancer Center
      • • Department of Pediatrics
      • • Department of Medical Oncology
      Houston, TX, United States
  • 1993
    • Medical University of South Carolina
      • Division of Oral Pathology
      Charleston, South Carolina, United States
  • 1990
    • University of Houston
      Houston, Texas, United States
    • Geisel School of Medicine at Dartmouth
      Hanover, New Hampshire, United States
  • 1989
    • University of Alberta
      Edmonton, Alberta, Canada
  • 1988
    • Tom Baker Cancer Centre
      Calgary, Alberta, Canada
  • 1985–1988
    • St. Jude Children's Research Hospital
      • • Department of Pharmaceutical Sciences
      • • Department of Hematology
      Memphis, Tennessee, United States
  • 1984
    • The University of Calgary
      • Faculty of Medicine
      Calgary, Alberta, Canada