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1
Whitehead, VM, DS Rosenblatt, MJ Vuchich, JJ Shuster, A. Witte, and D. Beaulieu. "Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis." Blood 76, no. 1 (July 1, 1990): 44–49. http://dx.doi.org/10.1182/blood.v76.1.44.44.
Full textAbstract:
Abstract Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized “good-risk” patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the “good-risk” children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for “good-risk” patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.
2
Whitehead, VM, DS Rosenblatt, MJ Vuchich, JJ Shuster, A. Witte, and D. Beaulieu. "Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis." Blood 76, no. 1 (July 1, 1990): 44–49. http://dx.doi.org/10.1182/blood.v76.1.44.bloodjournal76144.
Full textAbstract:
Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized “good-risk” patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the “good-risk” children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for “good-risk” patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.
3
Little, L., M. Alcouloumre, A. M. Drotar, S. Herman, R. Robertson, R. Y. Yeh, and A. L. Miller. "Properties of N-acetylglucosamine 1-phosphotransferase from human lymphoblasts." Biochemical Journal 248, no. 1 (November 15, 1987): 151–59. http://dx.doi.org/10.1042/bj2480151.
Full textAbstract:
Human lymphoblast and fibroblast cell lines from a patient with I-cell disease and normal individuals were characterized with respect to certain properties of UDP-N-acetylglucosamine:lysosomal enzyme precursor N-acetylglucosamine phosphotransferase. The enzyme isolated from normal lymphoblast and fibroblast cell lines expressed similar kinetic properties, substrate specificities and subcellular localizations. Coincident with the severe reduction of N-acetylglucosamine phosphotransferase activity in both I-cell fibroblast and lymphoblast cell lines, there was an increased secretion of several lysosomal enzymes compared to normal controls. Subsequent examination of N-acetyl-beta-D-hexosaminidase secreted by the I-cell lymphoblasts demonstrated a significant increase in adsorption of the I-cell enzyme to Ricinus communis agglutinin, a galactose-specific lectin. However, the I-cell lymphoblasts did not exhibit the significant decrease in intracellular lysosomal activities seen in I-cell fibroblasts. Our results suggest that lymphoblasts not only represent an excellent source for the purification of N-acetylglucosamine phosphotransferase, but in addition, represent a unique system for studying alternate mechanisms involved in the targeting of lysosomal enzymes.
4
Prokop, Aram, Banu Bagci, Guenaelle Lingfeld, Lucia Badiali, Karin Garbrecht, Ulrike Mietzsch, Thomas Wieder, Peter T. Daniel, and Günter Henze. "Sensitivity of Childhood Acute Lymphoblastic Leukemia (ALL) to Idarubicin Is Significantly Higher Than to Daunorubicin Treatment Based on Ex Vivo Apoptosis Induction." Blood 104, no. 11 (November 16, 2004): 4495. http://dx.doi.org/10.1182/blood.v104.11.4495.4495.
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Abstract Anthracyclines, especially daunorubicin, play a very important role in the treatment of acute lymphoblastic leukemia (ALL) and the relapsed ALL in childhood. In the present study, primary lymphoblasts isolated from 65 children with de novo ALL (median: 5.8 years; range: 1.9 – 16.9 years) and relapsed ALL (median: 12.7 years; range: 1.3 – 17.9 years) were treated with daunorubicin (10 mmol/l) or idarubicin (2 mmol/l) in vitro. We could show that both anthracylines induce apoptosis, as evidenced by measurement of genomic DNA fragmentation. Interestingly, daunorubicin only induced modest apoptosis, whereas idarubicin displayed a significantly stronger apoptosis inducing effect. Furthermore the treatment of daunorubicin-resistant lymphoblasts with idarubicin resulted in good response in most of the resistant cell populations. Out of the 65 patients analysed in this study 23 were female (13 de novo ALL, 10 relapsed ALL) and 42 were male (29 de novo ALL, 13 relapsed ALL). Primary lymphoblasts were obtained by bone marrow aspiration and separated by centrifugation over Ficoll. Within these cell populations following immunologic subgroups were found: 35 c-ALL, 10 pre-B-ALL, 7 pro-B-ALL, 10 T-ALL and 3 pre-T-ALL. Daunorubicin induced apoptosis in 33 out of 65 lymphoblast populations (response rate 50.8 %). Nevertheless, a far higher response rate was observed for idarubicin with 59/65 (90,8 %) (p < 0.008), if response is defined as apoptosis induction higher than 1 %. Daunorubicin-resistance was found in 32/65 (49,2 %), resistance to both was observed in 6/65 (9,2 %). Treatment of daunorubicin-resistant lymphoblasts with idarubicin resulted in significant apoptosis induction in 26 out of 32 cell populations (81,3 %). We clearly demonstrated here that the in vitro treatment of lymphoblasts from children with de novo or relapsed ALL with idarubicin induces significantly higher response rates than daunorubicin treatment. The ex vivo sensitivity of daunorubicin-resistant lymphoblasts of childhood ALL to idarubicin treatment reflects the better potency of idarubicin to induce apoptosis and to overcome daunorubicin resistance. These data prompted us to study the clinical relevance of idarubicin in ongoing clinical trials to improve existing therapeutic regiments. First clinical data point to a good tolerability of idarubicin in the treatment of relapsed ALL in childhood.
5
Katik, Banu, Anja Selig, Janna Velder, Elvira E. Shults, Thomas Wieder, Guenter Henze, Hans-Guenther Schmalz, and Aram Prokop. "New Pinostilbene Analogues Overcome Anthracycline Resistance in Acute Lymphoplastic Leukemia Ex Vivo." Blood 108, no. 11 (November 16, 2006): 4403. http://dx.doi.org/10.1182/blood.v108.11.4403.4403.
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Abstract Anthracylines play a very important role in the treatment of acute lymphoblastic leukemia (ALL) and relapsed ALL in childhood, however resistance to anthracyclines leads to a poor prognosis. In the present study, we have synthesized two new pinostilbene analogues, i.e. trans-3,4′-dihydroxy-5-methoxystilbene and (E)-resveratrol 4′-O-ß-D-glucopyranoside, which are able to overcome anthracycline resistance in childhood acute lymphoblastic leukemia (ALL) ex vivo and induce apoptosis in established leukemia cell lines via mitochondrial pathway. Apoptosis induction has been investigated by flowcytometric measurement of DNA-fragmentation [LC 50: 10 μM for (1) and (2)], mitochondrial membrane potential reduction and phosphatedylserin-staining on cell membrane surface. Cell death by necrosis could be excluded by a lactatdehydrogenase-release assay. For the first time we analysed the antileukemic and chemopreventive potentials of the pinostilbene analogues (1) and (2) ex vivo in a significant number of primary lymphoblasts of patients suffering from childhood ALL. Patients: Primary lymphoblasts isolated from 22 children with de novo ALL (median: 6.8 years; range 0,6–16.9 years) and relapsed ALL (median:7.2 years) were tested for ex vivo drug response with the anthracyclines daunorubicin (10 μmol/l) and doxorubicin (10 μmol/l) and two new pinostilbene analogues (1) and (2) (10μmol/l), according to their LC50 values in established cell lines. We could demonstrate in these primary cells that the pinostilbenes (1) and (2) were even more effective as compared with the anthracyclines. Out of 22 patients 14 were female (14 de novo ALL) and 8 were male (6 de novo ALL, 2 relapsed ALL). Within these cell populations following immunologic subgroups were found: c-ALL, pre-B-ALL, pro-B-ALL, T-ALL and pre-T-ALL. Results: Daunorubicin induced apoptosis in 6 out of 22 lymphoblast populations (response rate 27,3 %). A similar response rate was observed after treatment with doxorubicin: only 5 of 22 lymphoblast populations responded (22,7%). Nevertheless, far higher response rates were observed for (1) with 11/15 (73,3 %; p<0.005) and for (2) with 15/17 (88,2%; p<0.0002, all p-values by t-test). Interestingly, treatment of daunorubicin-resistant lymphoblasts resulted in significant apoptosis induction in 6 out of 10 cell populations after treatment with compound (1) (response rate 60 %) and in 6/6 after treatment with compound (2) (response rate 100%). Furthermore, pinostilbene (2) showed significant synergistic activity with daunorubicin in 2 of 3 lymphoblast populations. We clearly demonstrated that the ex vivo treatment of lymphoblasts from children with de novo and relapsed ALL with the new pinostilbenes (1) and (2) induced significantly higher response rates than daunorubicin or doxorubicin treatment. In conclusion, the high ex vivo sensitivity of anthracycline resistant leukemia cells to pinostilbene treatment reveals the great proapoptotic and chemopreventive potential of this new class of antileukemic agents.
6
Maslak, P. "Lymphoblasts." ASH Image Bank 2004, no. 0202 (February 2, 2004): 100992. http://dx.doi.org/10.1182/ashimagebank-2004-100992.
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7
Whitehead, VM, MJ Vuchich, SJ Lauer, D. Mahoney, AJ Carroll, JJ Shuster, DW Esseltine, C. Payment, AT Look, and J. Akabutu. "Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study." Blood 80, no. 5 (September 1, 1992): 1316–23. http://dx.doi.org/10.1182/blood.v80.5.1316.bloodjournal8051316.
Full textAbstract:
Hyperdiploidy (greater than 50 chromosomes, or a DNA index greater than 1.16) confers a favorable prognosis in B-lineage acute lymphoblastic leukemia of childhood. Children with B-lineage acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) in vitro experience a better event-free survival than those whose lymphoblasts do not (Blood 76:44, 1990). Lymphoblasts from 13 children with hyperdiploidy (greater than 50 chromosomes) accumulated high levels of MTX-PGs (1,095 and 571 to 2,346 pmol/10(9) cells [median and 25% to 75% intraquartile range]). These levels were higher than those in B-lineage lymphoblasts from 19 children with other aneuploidy (326 and 159 to 775 pmol/10(9) cells) and 15 children with diploidy (393 and 204 to 571 pmol/10(9) cells) (P = .0015). Chromosomal trisomies in hyperdiploid cases were highly nonrandom. Chromosome 9 was not one of the chromosomes involved in trisomies, even though this chromosome contains the gene for folate polyglutamate synthetase, which is the enzyme required for MTXPG synthesis. The correlation between MTXPG level and percentage of S- phase cells was weak, suggesting that increased levels of MTXPGs could not be attributed to elevated proportions of cells in active DNA synthesis. The ability of hyperdiploid lymphoblasts to accumulate high levels of MTXPGs may increase their sensitivity to MTX cytotoxicity, accounting in part for the improved outlook for hyperdiploid patients treated with regimens that emphasize MTX as a primary component of continuation therapy.
8
Schwartz, C. L., C. P. Minniti, P. Harwood, S. Na, M. L. Banquerigo, L. C. Strauss, J. Kurtzberg, S. D. Smith, and C. I. Civin. "Elimination of clonogenic malignant human T cells using monoclonal antibodies in combination with 2'-deoxycoformycin." Journal of Clinical Oncology 5, no. 12 (December 1987): 1900–1911. http://dx.doi.org/10.1200/jco.1987.5.12.1900.
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2'Deoxycoformycin (dCF) specifically inhibits adenosine deaminase (ADA) and causes selective cytotoxicity of normal and malignant T cells. In clinical trials, dCF caused rapid lysis of malignant T lymphoblasts. Although dCF has been associated with dose-limiting nonhematopoietic toxicities, myelosuppression has not been observed. Since dCF is relatively nontoxic to hematopoietic stem cells, we tested dCF for utility in the ex vivo purging of malignant T lymphoblasts from remission leukemic bone marrow for autologous bone marrow transplantation. We found that T lymphoblast cell lines were sensitive to dCF (plus deoxyadenosine [dAdo]) under conditions that did not ablate human hematopoietic colony-forming cells. Moreover, combined pharmacologic (dCF plus dAdo) and immunologic (anti-T cell monoclonal antibodies [McAb] plus complement) purging resulted in additive reduction in clonogenic T lymphoblasts. These results provide the basis for a clinical trial of bone marrow transplantation using combined pharmacologic/immunologic purging of T lymphoblasts from patients' harvested autologous marrow.
9
Sandlund, John T., Patricia L. Harrison, Gaston Rivera, Frederick G. Behm, David Head, James Boyett, Jeffrey E. Rubnitz, et al. "Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia." Blood 100, no. 1 (July 1, 2002): 43–47. http://dx.doi.org/10.1182/blood.v100.1.43.
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Abstract We determined the prognostic importance of morphologically identifiable persistent disease at day 15 and days 22 to 25 of remission induction in childhood acute lymphoblastic leukemia (ALL). Among 546 patients entered on 2 consecutive protocols, 397 patients had evaluable bone marrow (BM) examinations on day 15 (± 1 day) and 218 on days 22 to 25 (± 1 day). Fifty-seven patients (14%) had persistent lymphoblasts (≥ 1%) in the BM on day 15 and 27 patients (5.5%) had persistent lymphoblasts on days 22 to 25. The 5-year event-free survival (EFS) was significantly worse for patients with lymphoblasts on day 15 (40% ± 6%) or on days 22 to 25 (4% ± 3%) as compared to those without lymphoblasts on these dates (78% ± 2% and 76% ± 2%, respectively, P < .001 for both comparisons). A worse prognosis was observed even for patients with a low percentage of lymphoblasts (ie, 1%-4%) at either day 15 (5-year EFS = 56% ± 8%) or days 22 to 25 (5-year EFS = 0%) compared to those without morphologically identifiable persistent lymphoblasts at these times (P < .001 for both comparisons). The prognostic impact of persistent lymphoblasts on both dates remained significant after adjusting for other known risk factors, including treatment protocol, age, white blood cell count, DNA index, cell lineage, and central nervous system status, and National Cancer Institute/Rome criteria simultaneously. Hence, persistence of lymphoblasts (even 1%-4%) on day 15 of remission induction was associated with a poor prognosis and on days 22 to 25 signified a particularly dismal outcome; these very high-risk patients require novel or more intensive therapy to improve outcome.
10
Homans, AC, EN Forman, and BE Barker. "Use of monoclonal antibodies to identify cerebrospinal fluid lymphoblasts in children with acute lymphoblastic leukemia." Blood 66, no. 6 (December 1, 1985): 1321–25. http://dx.doi.org/10.1182/blood.v66.6.1321.1321.
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Abstract The identification of small numbers of leukemic cells in the cerebrospinal fluid (CSF) presents a diagnostic problem in the treatment of children with acute lymphoblastic leukemia (ALL). We adapted a latex sphere rosetting technique to allow us to identify simultaneously cell surface markers and cell morphology in 199 CSF samples from 34 patients and 14 control subjects. In patients without leukemic meningitis, the majority of CSF lymphocytes (69%) were found to be mature T cells positive for OKT11. A much smaller number of cells (8%) were found to be B cells positive for la. In these children, only 3% of CSF lymphoid cells expressed the common acute lymphoblastic leukemia antigen (CALLA). Similar results were found in the control subjects. By contrast, 28 CSF samples from nine children with varying numbers of CSF lymphoblasts had much greater proportions of CALLA- and la-positive CSF cells (24% to 96%). Leukemic meningitis was present in one of these patients and later developed in four others. However, three patients with small numbers of lymphoblasts present but with low proportions of CALLA-positive CSF cells (less than 5%) subsequently had normal CSF examinations. We found the use of this rosetting technique valuable in providing information complementary to that obtained from cell morphology alone about the possible malignant nature of small numbers of lymphoblast-like CSF cells seen on cytocentrifuge preparations in children with ALL.
11
Homans, AC, EN Forman, and BE Barker. "Use of monoclonal antibodies to identify cerebrospinal fluid lymphoblasts in children with acute lymphoblastic leukemia." Blood 66, no. 6 (December 1, 1985): 1321–25. http://dx.doi.org/10.1182/blood.v66.6.1321.bloodjournal6661321.
Full textAbstract:
The identification of small numbers of leukemic cells in the cerebrospinal fluid (CSF) presents a diagnostic problem in the treatment of children with acute lymphoblastic leukemia (ALL). We adapted a latex sphere rosetting technique to allow us to identify simultaneously cell surface markers and cell morphology in 199 CSF samples from 34 patients and 14 control subjects. In patients without leukemic meningitis, the majority of CSF lymphocytes (69%) were found to be mature T cells positive for OKT11. A much smaller number of cells (8%) were found to be B cells positive for la. In these children, only 3% of CSF lymphoid cells expressed the common acute lymphoblastic leukemia antigen (CALLA). Similar results were found in the control subjects. By contrast, 28 CSF samples from nine children with varying numbers of CSF lymphoblasts had much greater proportions of CALLA- and la-positive CSF cells (24% to 96%). Leukemic meningitis was present in one of these patients and later developed in four others. However, three patients with small numbers of lymphoblasts present but with low proportions of CALLA-positive CSF cells (less than 5%) subsequently had normal CSF examinations. We found the use of this rosetting technique valuable in providing information complementary to that obtained from cell morphology alone about the possible malignant nature of small numbers of lymphoblast-like CSF cells seen on cytocentrifuge preparations in children with ALL.
12
Whitehead, VM, MJ Vuchich, SJ Lauer, D. Mahoney, AJ Carroll, JJ Shuster, DW Esseltine, C. Payment, AT Look, and J. Akabutu. "Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study." Blood 80, no. 5 (September 1, 1992): 1316–23. http://dx.doi.org/10.1182/blood.v80.5.1316.1316.
Full textAbstract:
Abstract Hyperdiploidy (greater than 50 chromosomes, or a DNA index greater than 1.16) confers a favorable prognosis in B-lineage acute lymphoblastic leukemia of childhood. Children with B-lineage acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) in vitro experience a better event-free survival than those whose lymphoblasts do not (Blood 76:44, 1990). Lymphoblasts from 13 children with hyperdiploidy (greater than 50 chromosomes) accumulated high levels of MTX-PGs (1,095 and 571 to 2,346 pmol/10(9) cells [median and 25% to 75% intraquartile range]). These levels were higher than those in B-lineage lymphoblasts from 19 children with other aneuploidy (326 and 159 to 775 pmol/10(9) cells) and 15 children with diploidy (393 and 204 to 571 pmol/10(9) cells) (P = .0015). Chromosomal trisomies in hyperdiploid cases were highly nonrandom. Chromosome 9 was not one of the chromosomes involved in trisomies, even though this chromosome contains the gene for folate polyglutamate synthetase, which is the enzyme required for MTXPG synthesis. The correlation between MTXPG level and percentage of S- phase cells was weak, suggesting that increased levels of MTXPGs could not be attributed to elevated proportions of cells in active DNA synthesis. The ability of hyperdiploid lymphoblasts to accumulate high levels of MTXPGs may increase their sensitivity to MTX cytotoxicity, accounting in part for the improved outlook for hyperdiploid patients treated with regimens that emphasize MTX as a primary component of continuation therapy.
13
Cavallo, F., M. Forni, C. Riccardi, A. Soleti, F. Di Pierro, and G. Forni. "Growth and spread of human malignant T lymphoblasts in immunosuppressed nude mice: a model for meningeal leukemia." Blood 80, no. 5 (September 1, 1992): 1279–83. http://dx.doi.org/10.1182/blood.v80.5.1279.1279.
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Abstract Previous work has shown that nude (nu/nu) mice additionally immunosuppressed by splenectomy, sublethal irradiation, and treatment with antiasialo GM1 antiserum (SIA-nu/nu mice) have no detectable natural killer activity and allow the growth of human malignant lymphoblasts. We show here that all SIA-nu/nu mice engrafted intravenously with 5 x 10(6) malignant lymphoblasts originally derived from a child with a T-cell acute lymphoblastic leukemia (PF382) and from a boy with a T-cell lymphoma (ST-4) develop lethal meningeal leukemia and die within 35 days. Histologic examination of moribund SIA- nu/nu mice showed that vertebral and skull bone marrow was always replaced by proliferating human T lymphoblasts. From the spinal canal, lymphoblasts spread to the meninges, causing hind leg paralysis. Leaving the skull, they permeated the meninges and then invaded the nervous parenchyma. This efficient and reproducible experimental model may be suitable for experimental studies on the pathogenesis of meningeal leukemia.
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Cavallo, F., M. Forni, C. Riccardi, A. Soleti, F. Di Pierro, and G. Forni. "Growth and spread of human malignant T lymphoblasts in immunosuppressed nude mice: a model for meningeal leukemia." Blood 80, no. 5 (September 1, 1992): 1279–83. http://dx.doi.org/10.1182/blood.v80.5.1279.bloodjournal8051279.
Full textAbstract:
Previous work has shown that nude (nu/nu) mice additionally immunosuppressed by splenectomy, sublethal irradiation, and treatment with antiasialo GM1 antiserum (SIA-nu/nu mice) have no detectable natural killer activity and allow the growth of human malignant lymphoblasts. We show here that all SIA-nu/nu mice engrafted intravenously with 5 x 10(6) malignant lymphoblasts originally derived from a child with a T-cell acute lymphoblastic leukemia (PF382) and from a boy with a T-cell lymphoma (ST-4) develop lethal meningeal leukemia and die within 35 days. Histologic examination of moribund SIA- nu/nu mice showed that vertebral and skull bone marrow was always replaced by proliferating human T lymphoblasts. From the spinal canal, lymphoblasts spread to the meninges, causing hind leg paralysis. Leaving the skull, they permeated the meninges and then invaded the nervous parenchyma. This efficient and reproducible experimental model may be suitable for experimental studies on the pathogenesis of meningeal leukemia.
15
Agarwal, Prasoon, Laura Cole, Abin Chandrakumar, Kristin Hauff, Amir Ravandi, Vernon Dolinsky, and Grant Hatch. "Phosphokinome Analysis of Barth Syndrome Lymphoblasts Identify Novel Targets in the Pathophysiology of the Disease." International Journal of Molecular Sciences 19, no. 7 (July 12, 2018): 2026. http://dx.doi.org/10.3390/ijms19072026.
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Barth Syndrome (BTHS) is a rare X-linked genetic disease in which the specific biochemical deficit is a reduction in the mitochondrial phospholipid cardiolipin (CL) as a result of a mutation in the CL transacylase tafazzin. We compared the phosphokinome profile in Epstein-Barr-virus-transformed lymphoblasts prepared from a BTHS patient with that of an age-matched control individual. As expected, mass spectrometry analysis revealed a significant (>90%) reduction in CL in BTHS lymphoblasts compared to controls. In addition, increased oxidized phosphatidylcholine (oxPC) and phosphatidylethanolamine (PE) levels were observed in BTHS lymphoblasts compared to control. Given the broad shifts in metabolism associated with BTHS, we hypothesized that marked differences in posttranslational modifications such as phosphorylation would be present in the lymphoblast cells of a BTHS patient. Phosphokinome analysis revealed striking differences in the phosphorylation levels of phosphoproteins in BTHS lymphoblasts compared to control cells. Some phosphorylated proteins, for example, adenosine monophosphate kinase, have been previously validated as bonafide modified phosphorylation targets observed in tafazzin deficiency or under conditions of reduced cellular CL. Thus, we report multiple novel phosphokinome targets in BTHS lymphoblasts and hypothesize that alteration in the phosphokinome profile may provide insight into the pathophysiology of BTHS and potential therapeutic targets.
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Salzberg, Dana B., Amy K. Keating, Jian-zhe Cao, Susan Sather, Kimberley Hill, Adil Anwar, and Douglas K. Graham. "Ectopic Expression of Mer Receptor Tyrosine Kinase in Childhood T Cell Acute Lymphoblastic Leukemia." Blood 104, no. 11 (November 16, 2004): 4310. http://dx.doi.org/10.1182/blood.v104.11.4310.4310.
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Abstract Tyrosine kinases play an important role in normal cellular growth and differentiation. Deregulation of tyrosine kinase activity can result in cellular transformation leading to the development of human cancer. The Mer receptor tyrosine kinase, initially cloned from a human B lymphoblastoid cell line, is expressed in a spectrum of hematopoetic, epithelial, and mesenchymal cell lines. Interestingly, while the RNA transcript of Mer is detected in numerous T and B lymphoblastic cell lines, Mer RNA is not found in normal human thymocytes, lymphocytes or in PMA/PHA stimulated lymphocytes. We have developed an anti-human Mer monoclonal antibody to further study the ectopic Mer expression in lymphoblasts. The antibody detects several forms of the Mer protein including a fully glycosylated 205 kD Mer protein in monocytes and a less glycosylated 170–180 kD Mer protein in acute lymphoblastic leukemia (ALL) cell lines. We analyzed lymphoblasts from 16 T cell ALL patients diagnosed between July 1995 and July 2004 at The Children’s Hospital, Denver for Mer protein surface expression. Of the T cell ALL patient samples, we found that 9/16 (56%) were positive for Mer protein surface expression. Although we were not able to statistically evaluate the clinical outcomes relative to Mer expression due to the study sample number, there was a statistically significant association between positive expression of Mer and lack of surface expression of CD3 (p = 0.035). We found that 7/9 (78%) of the Mer positive lymphoblasts lacked CD3 surface expression, while only 1/6 (17%) of the Mer negative samples lacked CD3 surface expression (see figure). Lymphoblasts that lack surface expression of CD3 represent an immature phenotype and have been associated with a decreased event free survival as compared with surface positive CD3 lymphoblasts. Further investigation of the ectopic expression of Mer in lymphoblasts may reveal the use of this novel Mer glycosylated protein as a prognostic marker and possibly a future therapeutic target in the treatment of childhood leukemia. Figure Figure
17
Madabhavi, Irappa, Mitul Modi, Malay Sarkar, Sandeep K S, Mansi Shah, and Vinay Sakaleshpura Mallikarjuna. "Cancrum Oris(Noma): An Early Sign of Acute Lymphoblastic Leukemia Relapse." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S49. http://dx.doi.org/10.1093/ajcp/aqz113.030.
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Abstract Cancrum oris is an infectious disease, which involves the orofacial tissues and adjacent neighboring structures in its fulminant course. Cancrum oris can occur rarely in chemotherapy-induced neutropenic patients with acute lymphoblastic leukemia. This rare case report reveals that cancrum oris can be a sign of acute lymphoblastic leukemia relapse. It is characterized by gangrenous lesions on skin with fine-needle aspiration cytology smear from the lesion showing infiltration of lymphoblasts. Cancrum oris can occur rarely in chemotherapy-induced neutropenic patients with acute lymphoblastic leukemia, but the presentation as an early sign of extramedullary disease relapse has not been documented in literature. Here we report a case of cancrum oris in a 27-year-old woman who presented with redness and swelling of the upper lip and infranasal area. She had a known case of acute lymphoblastic leukemia diagnosed 6 months back and was on regular multiagent chemotherapy for the same. Clinical examination revealed gangrenous lesions on infranasal, intranasal, and area involving the upper lip. Complete blood count, bone marrow aspiration, and cytology did not show any lymphoblasts. Blood culture and swab culture from the gangrenous area were sterile. Patient did not get better even after 7 days of broad-spectrum antibiotic treatment. With a high degree of clinical suspicion of isolated extramedullary relapse, fine-needle aspiration cytology from marginal and gangrenous area was taken and revealed infiltration of soft tissues by lymphoblasts. After receiving four cycles of multiple chemotherapy drugs, the skin lesions resolved. Treatment of cancrum oris involves the correction of the underlying immune status, antibiotics, and surgical reconstruction. The rare possibility of relapse of acute lymphoblastic leukemia presenting as cancrum oris should be kept in mind in patients with acute lymphoblastic leukemia on chemotherapy with skin manifestations.
18
Dustin, M. L., K. H. Singer, D. T. Tuck, and T. A. Springer. "Adhesion of T lymphoblasts to epidermal keratinocytes is regulated by interferon gamma and is mediated by intercellular adhesion molecule 1 (ICAM-1)." Journal of Experimental Medicine 167, no. 4 (April 1, 1988): 1323–40. http://dx.doi.org/10.1084/jem.167.4.1323.
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The cell surface expression and function of the LFA-1 ligand, intercellular adhesion molecule 1 (ICAM-1), on epidermal keratinocytes (EK) was studied. ICAM-1 expression on the surface of cultured EK was either absent or weak, but was induced by treating EK with rIFN-gamma or TNF for 4-48 h. IFN-gamma and TNF were synergistic. IFN-gamma treatment increased T lymphoblast adhesion from less than 2% to 20-40%, with a concentration dependence similar to that seen for ICAM-1 induction. All of the adhesion to EK was inhibited by LFA-1 and ICAM-1 mAbs, but not by HLA-DR, CD2, or LFA-3 mAbs. There was no difference in the level of T lymphoblast adhesion to IFN-gamma-treated allogeneic or autologous EK. ICAM-1 purified from the HeLa epithelioid cell line and reconstituted into planar membranes also supported efficient adhesion of T lymphoblasts that was blocked by LFA-1 mAb bound to the T lymphoblasts or ICAM-1 mAb bound to the planar membranes. T lymphoblasts adherent to EK or ICAM-1 planar membranes were isolated by panning, and surface markers were analyzed by immunofluorescence flow cytometry. The adherent T cells were a phenotypically skewed subpopulation. They were enriched for CD8+ cells and expressed 1.5-2.5-fold higher LFA-1 and CD2 compared with the unseparated population.
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Rosskopf, Dieter, Markus Schürks, Iris Manthey, Markus Joisten, Stefan Busch, and Winfried Siffert. "Signal transduction of somatostatin in human B lymphoblasts." American Journal of Physiology-Cell Physiology 284, no. 1 (January 1, 2003): C179—C190. http://dx.doi.org/10.1152/ajpcell.00160.2001.
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Somatostatin (SST) and somatostatin receptors (SSTR) are widely distributed in lymphoid tissues. Here, we report on the stimulatory effects of SST in Epstein-Barr virus-immortalized B lymphoblasts. By RT-PCR, we demonstrated the exclusive expression of the somatostatin receptor isoform 2A (SSTR2A) in B lymphoblasts. Addition of SST rapidly increased the cytosolic free calcium concentration [Ca2+]imaximally by about 200 nM, with an EC50of 1.3 nM, and stimulated the formation of inositol phosphates. Furthermore, SST increased binding of guanosine 5′- O-(3-thiotriphosphate) by 50% above basal. These effects were partly inhibited by pertussis toxin (PTX), which indicates the involvement of PTX-sensitive G proteins. We provide further evidence that Gα16,a PTX-insensitive G protein confined to lymphohematopoietic cells, is involved in the otherwise unusual coupling of SSTR2A to phospholipase C activation. In addition, SST activated extracellular regulated kinases and induced a 3.5-fold stimulation of DNA synthesis and a 4.4-fold stimulation of B lymphoblast proliferation, which was accompanied by an enhanced immunoglobulin formation. Thus SST exerts a growth factor-like activity on human B lymphoblasts.
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Zhang, QiGuo, Jian Ouyang, and Jianyong Li. "Acute Lymphoblastic Leukemia with Mature Appearing Lymphocytes: First Chinese Case Report and Literature Review." Blood 112, no. 11 (November 16, 2008): 4896. http://dx.doi.org/10.1182/blood.v112.11.4896.4896.
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Abstract Objective: To increase the knowledge and understanding of acute lymphoblastic leukemia with maturation(ALLm). Method: One ALLm case with clinical manifestation, bone marrow morphology, immunophenotype and cytogenetic results were presented and related literatures were reviewed. Result: The patient was a fifty-five year old women, the haematological feature was Pancytopenia. There were 12% lymphoblasts and 82.5% mature appearing lymphocytes in the bone marrow smear. The mature appearing leukemic cells could not be separated clearly by gating. However, the immunophenotypes of mature-appearing leukemic cells(Low FSC and Low CD45) and lymphoblasts were the same. Both results were CD33+CD34+CD19+CD22+HLA−DR+CD5−CD7−CD10−CD13−CD14−CD15−CD20−CD25−CD45−CD71−CD11b−CD103−CD117−. Bone marrow biopsy showed hypercellularity with diffuse infiltration of lymphocytes, The results were CD34++,TdT++,Pax-5+++,CD43++,CD3+(scatter),CD5+(scatter),CD20−,CD10+,CyclinD1−, lymphoblasts Ki67+, mature-appearing leukemic cells ki-67-. FISH analysis of the bone marrow revealed about 1% cells with a signal pattern suggesting loss of one copy of chromosome 8. After VDP, MA, AAG and HAG regimens Complete remission was not achieved. Conclusion: ALLm is a special morphological variant of acute lymphoblastic leukemia, most mature appearing cells are in resting G0 phase and this could be the reason why ALLm has a poor response to chemotherapy.
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Neiman, P. E., C. Blish, C. Heydt, G. Loring, and S. J. Thomas. "Loss of cell cycle controls in apoptotic lymphoblasts of the bursa of Fabricius." Molecular Biology of the Cell 5, no. 7 (July 1994): 763–72. http://dx.doi.org/10.1091/mbc.5.7.763.
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Lymphoblasts of the normal embryonic follicles of the chicken bursa of Fabricius undergo rapid apoptosis when exposed to gamma-radiation or when cell-cell contacts are disrupted by mechanical dispersion in short term culture. We have observed previously that overexpression of v-myc sensitizes preneoplastic bursal lymphoblasts to induction of cell death, whereas resistance to induced cell death is acquired during progression to neoplasia. In this study we observed extensive DNA degradation in the large majority of the lymphoblast population within the first hour after dispersion-induced apoptosis. Paradoxically these cells continued to progress into S-phase with the bulk of DNA cleavage and death occurring in S-phase cells (i.e., in cells with more than 2C and less than 4C DNA content). We confirmed the S phase status of apoptotic cells by determining that detection of nuclear cyclin A in individual cells also corresponded with detection of DNA breakage. Levels of cyclin E, cyclin E-dependent H1 histone kinase, and p53 proteins were maintained during dispersion-induced DNA cleavage. gamma-radiation failed either to inhibit cell cycle progression or to raise p53 levels in dispersed bursal lymphoblasts. In intact bursal follicles low doses of gamma-radiation induced p53 whereas higher, apoptosis-inducing doses failed to induce p53 or prevent G1 to S-phase progression. These results suggest that normal DNA damage-induced cell cycle checkpoint controls are lost or overridden when apoptosis is induced in bursal lymphoblasts.
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Maitra, Anirban, and Arthur G. Weinberg. "Inclusions in Lymphoblasts." Pediatric and Developmental Pathology 1, no. 6 (November 1998): 573. http://dx.doi.org/10.1007/s100249900080.
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Lozanski, Gerard, Ben Sanford, Daohai Yu, Rebecca Pearson, Colin Edwards, John C. Byrd, Richard A. Larson, Clara D. Bloomfield, and Wendy Stock. "CD52 Expression in Adult Acute Lymphoblastic Leukemia (ALL): Quantitative Flow Cytometry Provides New Insights." Blood 108, no. 11 (November 1, 2006): 2293. http://dx.doi.org/10.1182/blood.v108.11.2293.2293.
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Abstract We recently tested the feasibility of incorporating Alemtuzumab, a humanized anti-CD52 monoclonal antibody, into frontline therapy of adult ALL (CALGB 10102) in an attempt to eradicate minimal residual disease (MRD). We have previously reported that CD52 expression occurs in 68% of newly diagnosed ALL. This assessment was based upon the use of a qualitative flow cytometric assay performed on all pre-treatment cases in a central CALGB reference laboratory. Cases with > 10% CD52 expression on lymphoblasts relative to an isotype control were considered CD52 positive and eligible to receive Alemtuzumab during post-remission therapy. To better characterize the CD52 expression level on lymphoblasts and to obtain insights for the design of future subset specific therapies in adult ALL, we developed a quantitative assay to measure CD52 antigen density on lymphoblasts using custom PE conjugated clinical grade Alemtuzumab on 29 cases of precursor B-cell (pre-B) ALL and 9 cases of precursor T-cell (pre-T) ALL. In this assay, CD52 is expressed in arbitrary units of antibody bound per cell (ABC). We also measured CD52 levels on residual normal B and T lymphocytes in every specimen to calculate a normalized ratio (NR) of lymphoblast CD52ABC/ normal lymphocytes CD52 ABC. The results are tabulated below: CD52 Expression Cell Type Precursor B-Cell ALL (n=29) median (range) Precursor T Cell ALL (n=9) median (range) CD52 ABC units Blasts 27658 (2042–206952) 10222 (3784–35337) CD52 ABC units Normal B Lymphocytes 125475 (59872–282245) 146478 (68098–291878) CD52 ABC units Normal T Lymphocytes 64142 (27406–141635) 78720 (22412–144350) CD52 NR Blasts/Normal B Lymphocytes 0.19 (0.02–0.88) 0.06 (0.02–0.16) CD52 NR Blasts/Normal T Lymphocytes 0.38 (0.04–2.16) 0.12 (0.07–0.26) Pre-B lymphoblasts express significantly lower levels of CD52 antigen than normal B lymphocytes (p<0.0001). Similarly, Pre-T lymphoblasts express significantly lower levels of CD52 antigen than the normal T lymphocytes (p<0.0001). Moreover, lymphoblasts in pre-T ALL show a near-significant lower expression of CD52 than pre-B lymphoblasts (two-sided p=0.05). Calculation of the NR confirms these observations. We have also begun to investigate CD52 expression by cytogenetic subset. Of note, we have determined that Philadelphia chromosome positive (Ph+) lymphoblasts were CD52+ in 26/28 (93%) cases studied; quantification of CD52 expression in Ph+ cases and in other common cytogenetic subsets is in progress. Correlation of CD52 expression with Alemtuzumab plasma levels and with development of opportunistic infections is underway. In conclusion, these data are the first to demonstrate that lymphoblasts from patients with untreated ALL express lower levels of CD52 antigen than residual normal lymphocytes present at the time of diagnosis. These findings may lead to improved selection of patients most likely to benefit from administration of Alemtuzumab and may have important implications for optimizing dosing and scheduling of Alemtuzumab during ALL therapy.
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Vargas, Sara O., Susan L. Hasegawa, and David M. Dorfman. "Hematogones as an Internal Control in Flow Cytometric Analysis of Suspected Acute Lymphoblastic Leukemia." Pediatric and Developmental Pathology 2, no. 4 (July 1999): 371–76. http://dx.doi.org/10.1007/s100249900137.
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Hematogones are benign immature B cells that commonly populate the bone marrow of children. Their presence has been noted to interfere with the flowcytometric analysis of cases of suspected acute lymphoblastic leukemia (ALL) because their immunophenotype (positive for CD19, CD10, CD34, and terminal deoxynucleotidyl transferase) is similar to that of pre–B cell lymphoblasts. Here we report a case in which the presence of a discrete population of hematogones, characterized by low-intensity CD10 cell-surface staining compared with pre–B cell lymphoblasts, actually aided in the recognition of early relapsed ALL and disease progression over a 4-day period. We also review our experience with flow-cytometric immunophenotyping in pediatric cases of suspected leukemia to evaluate the frequency of this occurrence.
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Dervieux, Thierry, Yaqin Chu, Yi Su, Ching-Hon Pui, William E. Evans, and Mary V. Relling. "HPLC Determination of Thiopurine Nucleosides and Nucleotides in Vivo in Lymphoblasts following Mercaptopurine Therapy." Clinical Chemistry 48, no. 1 (January 1, 2002): 61–68. http://dx.doi.org/10.1093/clinchem/48.1.61.
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Abstract Background: Mercaptopurine is a prodrug requiring intracellular activation to thiopurine nucleotides to exert antileukemic effect. We developed a reversed-phase liquid chromatographic assay for the quantification of mercaptopurine, thioguanine, and methylmercaptopurine nucleoside and nucleotide concentrations in the target tissue, the leukemic lymphoblast. Methods: Leukemic blasts were isolated from peripheral blood and bone marrow by a standard Ficoll-hypaque procedure. Proteins were removed by ultrafiltration in the presence of dithiothreitol. Thiopurine ribonucleotides were converted into their respective ribonucleosides by treatment of ultrafiltrate with acid phosphatase. Thiopurine nucleosides and bases were measured by direct injection of ultrafiltrate into the chromatographic system. Thiopurine nucleotide concentrations were calculated by subtracting the thiopurine nucleoside concentrations measured after treatment with acid phosphatase from those measured after direct injection of ultrafiltrate in the chromatographic system. Analytes were separated on a C18 Supelco column with ammonium phosphate-methanol eluent coupled with ultraviolet detection. Results: CVs for intra- and interday precision were 1.1–14% (median, 4.9%), and recovery of added analyte was 89–126% (median, 105%) at low and high concentrations of analytes, except for mercaptopurine riboside. The median signal for each of the five metabolites in lymphoblast samples was 98% (range, 80–106%) of that in water. Detection limits for thiopurine bases and nucleosides ranged from 0.5 to 4.5 pmol/5 × 106 cells. Conclusions: This method is suitable for measurement of thiopurine metabolite concentrations in lymphoblasts in children with acute lymphoblastic leukemia following a single dose of intravenous mercaptopurine.
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Chottiner, EG, D. Ginsburg, AP Tartaglia, and BS Mitchell. "Erythrocyte adenosine deaminase overproduction in hereditary hemolytic anemia." Blood 74, no. 1 (July 1, 1989): 448–53. http://dx.doi.org/10.1182/blood.v74.1.448.bloodjournal741448.
Full textAbstract:
A marked tissue-specific increase in erythrocyte adenosine deaminase (ADA) activity is associated with an autosomal dominantly inherited hemolytic anemia. We investigated the molecular basis of ADA overproduction by studying reticulocyte ADA mRNA from affected individuals. Analysis of proband reticulocyte ADA cDNA clones revealed normal sequence. RNase mapping demonstrated that the amount of ADA mRNA in affected reticulocytes was greater than the amount in normal B lymphoblasts, whereas ADA mRNA was undetectable in normal reticulocytes. The 5′- and 3′-untranslated regions of reticulocyte and B-lymphoblast ADA mRNAs from affected individuals were structurally indistinguishable from those of normal B lymphoblasts. Northern blot analysis performed under stringent hybridization and washing conditions confirmed a markedly increased amount of reticulocyte ADA mRNA in affected individuals as compared with controls. We conclude that the RBC-specific overexpression of ADA in this disorder occurs at the mRNA level.
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Babcock, Gregory J., Lisa L. Decker, Richard B. Freeman, and David A. Thorley-Lawson. "Epstein-Barr Virus–Infected Resting Memory B Cells, Not Proliferating Lymphoblasts, Accumulate in the Peripheral Blood of Immunosuppressed Patients." Journal of Experimental Medicine 190, no. 4 (August 16, 1999): 567–76. http://dx.doi.org/10.1084/jem.190.4.567.
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When Epstein-Barr virus (EBV) infects B cells in vitro, the result is a proliferating lymphoblast that expresses at least nine latent proteins. It is generally believed that these cells are rigorously controlled in vivo by cytotoxic T cells. Consistent with this, the latently infected cells in the peripheral blood of healthy carriers are not lymphoblasts. Rather, they are resting memory B cells that are probably not subject to direct immunosurveillance by cytotoxic T lymphocytes (CTLs). When patients become immunosuppressed, the viral load increases in the peripheral blood. The expansion of proliferating lymphoblasts due to the suppressed CTL response is believed to account for this increase and is considered to be a major risk factor for posttransplant lymphoproliferative disease (PTLD) and AIDS-associated B cell lymphoma. Here we show that there is an increase in the numbers of latently infected cells in the peripheral blood of immunosuppressed patients. However, the cells are not proliferating lymphoblasts. They are all latently infected, resting, memory B cells—the same population of infected cells found in the blood of healthy carriers. These results are discussed in the context of a model for EBV persistence that explains why PTLD is usually limited to the lymph nodes.
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Poli de Figueiredo, C. E., L. L. Ng, J. E. Davis, F. J. Lucio-Cazana, J. C. Ellory, and B. M. Hendry. "Modulation of Na-H antiporter activity in human lymphoblasts by altered membrane cholesterol." American Journal of Physiology-Cell Physiology 261, no. 6 (December 1, 1991): C1138—C1142. http://dx.doi.org/10.1152/ajpcell.1991.261.6.c1138.
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The effects of changes in membrane cholesterol on Na-H antiporter activity in culture human lymphoblasts are described. Lymphoblast cholesterol alteration was achieved with liposomes of phosphatidylcholine (cholesterol depletion) or phosphatidylcholine plus cholesterol (cholesterol enrichment). Lymphoblast intracellular pH (pHi) was examined by fluorimetry using cells loaded with the pH-sensitive dye 2',7'-bis(2-carboxyethyl)5(6)-carboxyfluorescein, and the Na-dependent proton efflux rate at a pHi of 6.0 was taken as the maximum velocity of the Na-H antiporter. Lymphoblast membrane cholesterol depletion activated the Na-H antiporter, and enrichment of membrane cholesterol caused inhibition of the antiporter activity. This study demonstrates that in situ modification of membrane cholesterol can modulate the activity of the Na-H antiporter.
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Eluka-Okoludoh, E., AJ Ewunkem, S. Thorpe, A. Blanchard, and P. Muganda. "Diepoxybutane-induced apoptosis is mediated through the ERK1/2 pathway." Human & Experimental Toxicology 37, no. 10 (February 6, 2018): 1080–91. http://dx.doi.org/10.1177/0960327118755255.
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Diepoxybutane (DEB) is the most potent active metabolite of butadiene, a regulated air pollutant. We previously reported the occurrence of DEB-induced, p53-dependent, mitochondrial-mediated apoptosis in human lymphoblasts. The present study investigated the role of the extracellular signal–regulated protein kinases 1 and 2 (ERK1/2) pathway in DEB-induced apoptotic signaling in exposed human lymphoblasts. Activated ERK1/2 and mitogen-activated protein (MAP) kinase/ERK1/2 kinase (MEK) levels were significantly upregulated in DEB-exposed human lymphoblasts. The MEK inhibitor PD98059 and ERK1/2 siRNA significantly inhibited apoptosis, ERK1/2 activation, as well as p53 and phospho-p53 (serine-15) levels in human lymphoblasts undergoing DEB-induced apoptosis. Collectively, these results demonstrate that DEB induces apoptotic signaling through the MEK-ERK1/2-p53 pathway in human lymphoblasts. This is the first report implicating the activation of the ERK1/2 pathway and its subsequent role in mediating DEB-induced apoptotic signaling in human lymphoblasts. These findings contribute towards the understanding of DEB toxicity, as well as the signaling pathways mediating DEB-induced apoptosis in human lymphoblasts.
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Bishop, David F., Xiaoye Schneider-Yin, Sonia Clavero, Han-Wook Yoo, Elisabeth I. Minder, and Robert J. Desnick. "Congenital erythropoietic porphyria: a novel uroporphyrinogen III synthase branchpoint mutation reveals underlying wild-type alternatively spliced transcripts." Blood 115, no. 5 (February 4, 2010): 1062–69. http://dx.doi.org/10.1182/blood-2009-04-218016.
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Abstract Splicing mutations account for approximately 10% of lesions causing genetic diseases, but few branchpoint sequence (BPS) lesions have been reported. In 3 families with autosomal recessive congenital erythropoietic porphyria (CEP) resulting from uroporphyrinogen III synthase (URO-synthase) deficiency, sequencing the promoter, all 10 exons and the intron/exon boundaries did not detect a mutation. Northern analyses of lymphoblast mRNAs from 2 patients and reverse-transcribed polymerase chain reaction (RT-PCR) of lymphoblast mRNAs from all 3 patients revealed multiple longer transcripts involving intron 9 and low levels of wild-type message. Sequencing intron 9 RT-PCR products and genomic DNA in each case revealed homozygosity for a novel BPS mutation (c.661-31T→G) and alternatively spliced transcripts containing 81, 246, 358, and 523 nucleotides from intron 9. RT-PCR revealed aberrant transcripts in both wild-type and CEP lymphoblasts, whereas BPS mutation reduced the wild-type transcript and enzyme activity in CEP lymphoblasts to approximately 10% and 15% of normal, respectively. Although the +81-nucleotide alternative transcript was in-frame, it only contributed approximately 0.2% of the lymphoblast URO-synthase activity. Thus, the BPS mutation markedly reduced the wild-type transcript and enzyme activity, thereby causing the disease. This is the first BPS mutation in the last intron, presumably accounting for the observed 100% intron retention without exon skipping.
31
Chottiner, EG, D. Ginsburg, AP Tartaglia, and BS Mitchell. "Erythrocyte adenosine deaminase overproduction in hereditary hemolytic anemia." Blood 74, no. 1 (July 1, 1989): 448–53. http://dx.doi.org/10.1182/blood.v74.1.448.448.
Full textAbstract:
Abstract A marked tissue-specific increase in erythrocyte adenosine deaminase (ADA) activity is associated with an autosomal dominantly inherited hemolytic anemia. We investigated the molecular basis of ADA overproduction by studying reticulocyte ADA mRNA from affected individuals. Analysis of proband reticulocyte ADA cDNA clones revealed normal sequence. RNase mapping demonstrated that the amount of ADA mRNA in affected reticulocytes was greater than the amount in normal B lymphoblasts, whereas ADA mRNA was undetectable in normal reticulocytes. The 5′- and 3′-untranslated regions of reticulocyte and B-lymphoblast ADA mRNAs from affected individuals were structurally indistinguishable from those of normal B lymphoblasts. Northern blot analysis performed under stringent hybridization and washing conditions confirmed a markedly increased amount of reticulocyte ADA mRNA in affected individuals as compared with controls. We conclude that the RBC-specific overexpression of ADA in this disorder occurs at the mRNA level.
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Spertini, Caroline, Bénédicte Baïsse, Marta Bellone, Milica Gikic, Tatiana Smirnova, and Olivier Spertini. "Acute Myeloid and Lymphoblastic Leukemia Cell Interactions with Endothelial Selectins: Critical Role of PSGL-1, CD44 and CD43." Cancers 11, no. 9 (August 27, 2019): 1253. http://dx.doi.org/10.3390/cancers11091253.
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Acute myeloid and lymphoblastic leukemia are poor prognosis hematologic malignancies, which disseminate from the bone marrow into the blood. Blast interactions with selectins expressed by vascular endothelium promote the development of drug resistance and leukostasis. While the role of selectins in initiating leukemia blast adhesion is established, our knowledge of the involved selectin ligands is incomplete. Using various primary acute leukemia cells and U937 monoblasts, we identified here functional selectin ligands expressed by myeloblasts and lymphoblasts by performing biochemical studies, expression inhibition by RNA interference and flow adhesion assays on recombinant selectins or selectin ligands immunoadsorbed from primary blast cells. Results demonstrate that P-selectin glycoprotein ligand-1 (PSGL-1) is the major P-selectin ligand on myeloblasts, while it is much less frequently expressed and used by lymphoblasts to interact with endothelial selectins. To roll on E-selectin, myeloblasts use PSGL-1, CD44, and CD43 to various extents and the contribution of these ligands varies strongly among patients. In contrast, the interactions of PSGL-1-deficient lymphoblasts with E-selectin are mainly supported by CD43 and/or CD44. By identifying key selectin ligands expressed by acute leukemia blasts, this study offers novel insight into their involvement in mediating acute leukemia cell adhesion with vascular endothelium and may identify novel therapeutic targets.
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Blankenberg, Francis G., Peter D. Katsikis, Richard W. Storrs, Christian Beaulieu, Daniel Spielman, James Y. Chen, Louie Naumovski, and Jonathan F. Tait. "Quantitative Analysis of Apoptotic Cell Death Using Proton Nuclear Magnetic Resonance Spectroscopy." Blood 89, no. 10 (May 15, 1997): 3778–86. http://dx.doi.org/10.1182/blood.v89.10.3778.3778_3778_3786.
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Quantification of apoptotic cell death in vivo has become an important area of investigation in patients with acute lymphoblastic leukemia (ALL). We have devised a noninvasive analytical method to estimate the percentage of apoptotic lymphoblasts in doxorubicin-treated Jurkat T-cell ALL cultures, using proton nuclear magnetic resonance spectroscopy (1H NMR). We have found that the ratio of the methylene (CH2 ) resonance (at 1.3 ppm) to the methyl (CH3 ) resonance (at 0.9 ppm) signal intensity, as observed by 1H NMR, is directly proportional to the percentage of apoptotic lymphoblasts in vitro. The correlation between the CH2/CH3 signal intensity ratio and the percentage of apoptotic lymphoblasts was optimal 24 to 28 hours after doxorubicin treatment (r2 = .947, N = 27 samples). There was also a direct temporal relationship between an increase in the CH2/CH3 signal intensity ratio and the onset of apoptosis as detected by nuclear morphologic analysis, fluorescein-annexin V flow cytometry, and DNA gel electrophoresis. Thin-layer chromatography confirmed that a dynamic and/or compositional change of the plasma membrane, rather than increases in lipase activity or fatty acid production, appears to account for the increase in the CH2/CH3 signal intensity ratio during apoptosis. 1H NMR may have clinical utility for the early noninvasive assessment of chemotherapeutic efficacy in patients with ALL.
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Finn, Laura S., Douglas S. Hawkins, Joe C. Rutledge, and Kathleen Patterson. "Evaluation of Early Marrow Response in Childhood Aneuploid Acute Lymphoblastic Leukemia: Flow Cytometric DNA Analysis versus Standard Morphology." Pediatric and Developmental Pathology 7, no. 1 (January 2004): 39–47. http://dx.doi.org/10.1007/s10024-003-2017-x.
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Despite improved survival rates for childhood acute lymphoblastic leukemia (ALL), the relapse rate remains at 20–30%. Early peripheral blood and bone marrow (BM) responses have been associated with more favorable outcomes; all current children's cancer group (CCG) protocols for ALL require BM evaluation at days 7 and 14 with subsequent therapy based on the results. Morphologic interpretation of aspirate smears during induction chemotherapy is challenging, as the samples are often hypocellular, excessively friable, and cytologically altered by drugs. We have shown discordancy of day 7 and 14 BM lymphoblast counts using morphologic and flow cytometric immunophenotypic analyses (FC). The aim of our study was to determine the utility, reliability, and cost effectiveness of lymphoblast enumeration using DNA content analysis by flow cytometry (DNA-FC) and to further demonstrate the subjectivity of morphologic review. All new cases of ALL had DNA-FC and FC analyses. The percentage of lymphoblasts as determined by both methods was compared for 82 aneuploid cases. Three pathologists independently reviewed aspirate smears from 39 bone marrow samples of aneuploid ALL that were obtained during early induction. These results were compared among themselves and with the results obtained by DNA-FC. We found excellent correlation between the percentage of lymphoblasts as determined by DNA-FC and FC (R2= 0.97) over a range of 0 to 99%. Pathologic review agreed with the DNA-FC, on average, 68%. The sensitivity, specificity, and positive and negative predictive values of morphologic review, averaged 53, 84, 78, and 63%, respectively, when using DNA-FC as the “gold standard.” All three pathologists achieved agreement of lymphoblast percentage by morphology in 72%. In our laboratory, the use of DNA-FC equates to one-sixth the time and one-half the price of FC per exam. We have shown a strong correlation between blast counts determined by DNA-FC and FC. DNA-FC is an objective, economical, and reliable method to assess early response in induction marrows from aneuploid ALL where morphology is often uninterpretable. This test is highly reproducible and available at most pediatric institutions. Prospective studies need to be employed to evaluate the effect of more definitive methods (DNA-FC and FC) of assessing the early response in bone marrows on prognosis.
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Matherly, LH, JW Taub, Y. Ravindranath, SA Proefke, SC Wong, P. Gimotty, S. Buck, JE Wright, and A. Rosowsky. "Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia." Blood 85, no. 2 (January 15, 1995): 500–509. http://dx.doi.org/10.1182/blood.v85.2.500.500.
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Abstract A retrospective study of clinical resistance to methotrexate (MTX) was performed on 29 archival specimens of frozen lymphoblasts obtained from children with acute lymphoblastic leukemia (ALL), including 19 at initial presentation and 10 at first relapse. Blasts were assayed for dihydrofolate reductase and MTX transport by flow cytometry using the fluorescent methotrexate analog, PT430 (Rosowsky et al, J Biol Chem 257:14162, 1982). In contrast to tissue culture cells, patient blasts were often heterogeneous for dihydrofolate reductase content. Of the 19 specimens at initial diagnosis, 7 exhibited dual blast populations, characterized by threefold to 10-fold differences in relative dihydrofolate reductase; the dihydrofolate reductase-overproducing populations comprised 12% to 68% of the total blasts for these specimens. Remission duration intervals for patients exhibiting dual blast populations were notably shorter than for patients expressing a single blast population with lower dihydrofolate reductase ( < or = 9 months v > or = 15 months, respectively), a difference that was statistically significant (P = .045). There was no apparent correlation between expression of increased dihydrofolate reductase at diagnosis and known patient and disease prognostic features (immunophenotype, age, sex, and white blood count). For the relapsed patients, 4 of 10 exhibited dual lymphoblast populations with elevated dihydrofolate reductase. The majority of the patient lymphoblast specimens were entirely competent for MTX transport and, likewise, expressed immunoreactive reduced folate carriers by indirect immunofluorescence staining with specific antiserum to the transporter. Three patients (2 at relapse and 1 at diagnosis) exhibited heterogeneous expression of imparied MTX transport (14% to 73% of blasts). In only 1 of these patients did the majority of the lymphoblasts (73%) show impaired MTX transport and for this specimen, immunoreactive carrier proteins were virtually undetectable. These results suggest that heterogeneous expression of elevated dihydrofolate reductase and impaired MTX transport are important modes of resistance in childhood ALL patients undergoing chemotherapy with MTX and that these parameters may serve as predictive indices of clinical response to MTX.
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Matherly, LH, JW Taub, Y. Ravindranath, SA Proefke, SC Wong, P. Gimotty, S. Buck, JE Wright, and A. Rosowsky. "Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia." Blood 85, no. 2 (January 15, 1995): 500–509. http://dx.doi.org/10.1182/blood.v85.2.500.bloodjournal852500.
Full textAbstract:
A retrospective study of clinical resistance to methotrexate (MTX) was performed on 29 archival specimens of frozen lymphoblasts obtained from children with acute lymphoblastic leukemia (ALL), including 19 at initial presentation and 10 at first relapse. Blasts were assayed for dihydrofolate reductase and MTX transport by flow cytometry using the fluorescent methotrexate analog, PT430 (Rosowsky et al, J Biol Chem 257:14162, 1982). In contrast to tissue culture cells, patient blasts were often heterogeneous for dihydrofolate reductase content. Of the 19 specimens at initial diagnosis, 7 exhibited dual blast populations, characterized by threefold to 10-fold differences in relative dihydrofolate reductase; the dihydrofolate reductase-overproducing populations comprised 12% to 68% of the total blasts for these specimens. Remission duration intervals for patients exhibiting dual blast populations were notably shorter than for patients expressing a single blast population with lower dihydrofolate reductase ( < or = 9 months v > or = 15 months, respectively), a difference that was statistically significant (P = .045). There was no apparent correlation between expression of increased dihydrofolate reductase at diagnosis and known patient and disease prognostic features (immunophenotype, age, sex, and white blood count). For the relapsed patients, 4 of 10 exhibited dual lymphoblast populations with elevated dihydrofolate reductase. The majority of the patient lymphoblast specimens were entirely competent for MTX transport and, likewise, expressed immunoreactive reduced folate carriers by indirect immunofluorescence staining with specific antiserum to the transporter. Three patients (2 at relapse and 1 at diagnosis) exhibited heterogeneous expression of imparied MTX transport (14% to 73% of blasts). In only 1 of these patients did the majority of the lymphoblasts (73%) show impaired MTX transport and for this specimen, immunoreactive carrier proteins were virtually undetectable. These results suggest that heterogeneous expression of elevated dihydrofolate reductase and impaired MTX transport are important modes of resistance in childhood ALL patients undergoing chemotherapy with MTX and that these parameters may serve as predictive indices of clinical response to MTX.
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Mullen, Craig A., and Olga Sevastianova. "Simulataneous Vaccination and Delayed Lymphocyte Infusion for Enhancement of Immune Reactivity Against Acute Lymphoblastic Leukemia or Lymphoma." Blood 106, no. 11 (November 16, 2005): 5248. http://dx.doi.org/10.1182/blood.v106.11.5248.5248.
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Abstract BACKGROUND: Delayed lymphocyte infusion (DLI) can be employed as an antileukemia immune therapy when patients with leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT). While effective in patients with chronic myelogenous leukemia, it is generally ineffective with relapse of acute lymphoblastic leukemia (ALL). This ineffectiveness may be multifactorial and possible reasons include rapid leukemia cell growth in ALL, reduced propensity to apoptosis signals, and poor presentation of antigens present on lymphoblasts resulting in failure to generate a significant immune response. If the failure of malignant lymphoblasts in marrow and lymphoid tissues to elicit meaningful T cell responses plays a role in the ineffectiveness of DLI, it is possible that therapeutic vaccines may be able to ameliorate this barrier. We have recently demonstrated that vaccination immediately prior to HSCT enhances antigen specific T cell responses in the post-transplant immune repertoire (Bone Marrow Transplantation, 35:793–801, 2005.) HYPOTHESIS: Vaccination with leukemia related antigens at the time of DLI will increase donor T cell responses to leukemia related antigens without exacerbation of GVHD responses to ubiquitous host minor histocompatibility antigens (mHA). METHODS: We employ a murine MHC matched allogeneic HSCT model in which 6 antigens are molecularly characterized. C3.SW mice are donors and C57BL/6 mice are recipients. In this model the H7 mHA is the immunodominant antigen, while alloresponses to H3 and H13 are also present. By using spontaneously arising lymphoblastic leukemia/lymphoma cells from Ig-cmyc transgenic male C57BL/6 as the model malignancy in a female to female transplant the male HY associated antigens Uty, Dby and Smcy can be used as antigens restricted to the lymphoid malignancy. Four weeks after allogeneic HSCT mice were vaccinated with 107 cells expressing the HY antigens and the C57BL/6 H7, H3 and H13 minor antigens. The cells used for pre-DLI vaccination were either irradiated male C57BL/6 spleen cells or irradiated male malignant lymphoblasts. One day later mice received iv infusion of 107 spleen cells from C3.SW female donor mice previously primed against HY antigens by immunization with male C3.SW cells. Ten days interferon gamma Elispot assays were performed on HSCT recipient spleen cells using the peptide-defined antigens. RESULTS: Vaccination of HSCT recipients with male spleen cells 1 day prior to DLI from HY immune donors significantly increased T cell responses to HY peptide epitopes. Recipients of DLI alone harbored 40 interferon secreting cells per 106, while combination of vaccination and DLI yielded 94 per 106(p < 0.05). In contrast, there was no change in the number of T cells responding to the H7, H3 and H13 mHA. DLI only exhibited 26 per 106 while DLI plus vaccine exhibited 27 per 106 (p < 0.05). Whole cell irradiated lymphoblasts were not as effective as irradiated splenocytes in augmenting the HY responses, although they were equally effective in producing T cell responses in normal, nontransplanted mice. CONCLUSIONS: Simultaneous vaccination and DLI can lead to significant expansion of donor cells potentially reactive with antigens present on malignant lymphoblasts without exacerbation of T cell responses to ubiquitous mHA associated with GVHD. Current work is exploring methods by which indirect presentation of antigens from lymphoblasts can be enhanced, since it is unlikely that vaccines relying on direct antigen presentation by lymphoblasts will be effective.
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Whitehead, V. Michael, David S. Rosenblatt, Mary-Jane Vuchich, and Denise Beaulieu. "Methotrexate Polyglutamate Synthesis in Lymphoblasts from Children with Acute Lymphoblastic Leukemia." Developmental Pharmacology and Therapeutics 10, no. 6 (1987): 443–48. http://dx.doi.org/10.1159/000457776.
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Hauff, Kristin D., and Grant M. Hatch. "Reduction in cholesterol synthesis in response to serum starvation in lymphoblasts of a patient with Barth syndromeThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 88, no. 4 (August 2010): 595–602. http://dx.doi.org/10.1139/o09-186.
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Barth syndrome is a rare X-linked disease in which mild hypocholesterolemia is observed in some patients. We investigated cholesterol biosynthesis in lymphoblasts from a normal and age-matched Barth syndrome patient. Control and Barth syndrome (ΔTAZ1) lymphoblasts were incubated in the presence or absence of serum to induce cholesterol synthesis and hydroxymethylglutaryl-coenzyme A reductase activity and expression, and cholesterol biosynthesis from radioactive precursors was determined. Cholesterol biosynthesis from [2-14C]pyruvate was stimulated 2-fold in control cells, but was unchanged in ΔTAZ1 lymphoblasts, and from [1-14C]acetate was stimulated 77% in control but only 26% in ΔTAZ1 lymphoblasts upon serum removal, indicating a lower ability of ΔTAZ1 cells to upregulate cholesterol biosynthesis. The reason was an inability to increase hydroxymethylglutaryl-coenzyme A reductase activity, which was already near maximum in ΔTAZ1 lymphoblasts, in response to serum removal, compared with control cells. The reduced ability to increase hydroxymethylglutaryl-coenzyme A reductase enzyme activity in ΔTAZ1 lymphoblasts was due to a decrease in hydroxymethylglutaryl-coenzyme A reductase messenger RNA. Although total cholesterol levels are similar under standard culture conditions, ΔTAZ1 lymphoblasts have a diminished capacity to respond to increased demand for cholesterol biosynthesis because of an already elevated level of synthesis under standard culture conditions.
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Blankenberg, Francis G., Peter D. Katsikis, Richard W. Storrs, Christian Beaulieu, Daniel Spielman, James Y. Chen, Louie Naumovski, and Jonathan F. Tait. "Quantitative Analysis of Apoptotic Cell Death Using Proton Nuclear Magnetic Resonance Spectroscopy." Blood 89, no. 10 (May 15, 1997): 3778–86. http://dx.doi.org/10.1182/blood.v89.10.3778.
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Abstract Quantification of apoptotic cell death in vivo has become an important area of investigation in patients with acute lymphoblastic leukemia (ALL). We have devised a noninvasive analytical method to estimate the percentage of apoptotic lymphoblasts in doxorubicin-treated Jurkat T-cell ALL cultures, using proton nuclear magnetic resonance spectroscopy (1H NMR). We have found that the ratio of the methylene (CH2 ) resonance (at 1.3 ppm) to the methyl (CH3 ) resonance (at 0.9 ppm) signal intensity, as observed by 1H NMR, is directly proportional to the percentage of apoptotic lymphoblasts in vitro. The correlation between the CH2/CH3 signal intensity ratio and the percentage of apoptotic lymphoblasts was optimal 24 to 28 hours after doxorubicin treatment (r2 = .947, N = 27 samples). There was also a direct temporal relationship between an increase in the CH2/CH3 signal intensity ratio and the onset of apoptosis as detected by nuclear morphologic analysis, fluorescein-annexin V flow cytometry, and DNA gel electrophoresis. Thin-layer chromatography confirmed that a dynamic and/or compositional change of the plasma membrane, rather than increases in lipase activity or fatty acid production, appears to account for the increase in the CH2/CH3 signal intensity ratio during apoptosis. 1H NMR may have clinical utility for the early noninvasive assessment of chemotherapeutic efficacy in patients with ALL.
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Wei, Van Renne, and Nauwynck. "Strain-Dependent Porcine Circovirus Type 2 (PCV2) Entry and Replication in T-Lymphoblasts." Viruses 11, no. 9 (September 2, 2019): 813. http://dx.doi.org/10.3390/v11090813.
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Porcine circovirus type 2 (PCV2) is the etiological agent of PCV2-associated diseases (PCVAD). PCV2 targets lymphoblasts, and pigs suffering from PCVAD display lymphocyte depletion in lymphoid tissues. PCV2 infection of lymphoblasts has not been studied. Here, the replication cycle of PCV2 (abortion strain 1121 and PMWS strain Stoon1010) in T-lymphoblasts was examined. The expression of Rep and Cap were found for both viral strains, while progeny virus was detected for Stoon1010 but not for 1121. PCV2 attached to 11–26% (1121-Stoon1010) of the T-lymphoblasts while 2.6–12.7% of cells showed virus internalization. Chondroitin sulfate (CS) was present on 25% of T-lymphoblasts, and colocalized with PCV2 on 31–32% of the PCV2+ cells. Enzymatic removal of CS reduced PCV2 infection. PCV2 infection was decreased by chlorpromazine, cytochalasin D and Clostridium difficile toxin B for both viral strains and by amiloride for 1121 but not for Stoon1010. Inhibiting either endosome acidification or serine proteases strongly reduced PCV2 infection. Three-dimensional analysis of Cap structure demonstrated a better Cap-nucleic acid affinity for Stoon1010 than for 1121. Taken together, PCV2 binds to T-lymphoblasts partially via CS, enters via clathrin-mediated endocytosis, and disassembles under functions of a pH-drop and serine proteases. Strain Stoon1010 displayed an enhanced viral binding, a specific receptor-mediated endocytosis, an increased Cap-nucleic acid affinity, and a more productive infection in T-lymphoblasts than 1121 did, indicating an evolution from 1121 to Stoon1010.
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Repetti, Charles, Hsueh-Hua Chen, Yongbao Wang, Vanessa A. Jones, Albert K. Ho, Qiulu Pan, Ila Bansal, and Dan Jones. "Impaired Precursor B-Cell Maturation/Production In The Bone Marrow: Association With Molecular and Immunophenotypic Markers Of Myeloid Dysplasia In Suspected Low-Grade MDS." Blood 122, no. 21 (November 15, 2013): 4943. http://dx.doi.org/10.1182/blood.v122.21.4943.4943.
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Abstract Rationale Myelodysplastic syndromes (MDS) are clonal stem cell disorders that disrupt orderly maturation of multiple hematopoietic lineages. Several studies have suggested that maturation of precursor B cells (hematogones) is also abnormal in MDS. As a result, the presence of normal numbers or increased precursor B cells in bone marrow (BM) is frequently used as a diagnostic feature arguing against a diagnosis of MDS. We compared the presence of myeloid-associated gene mutations and myeloid maturation abnormalities with qualitative and quantitative precursor B cell findings in BM samples submitted for workup of cytopenias or MDS. Methods Seventeen BM aspirate samples with <5% blasts submitted for cytopenia or MDS evaluation were compared with 10 samples having 5% or more blasts and changes diagnostic of MDS or AML. Mutation analysis was performed on genomic DNA using a targeted exome sequencing assay. This assay employs a TruSeq custom amplicon design on the MiSeq platform (Illumina, San Diego, CA). The assay covers the commonly mutated areas of 19 myeloid-associated genes. Somatic mutation status was assigned based on mutation levels, previous association with myeloid neoplasia, and no prior identification in public or internal databases as a normal sequence variant. Flow cytometry using 6-color (CD19/CD34) and 8-color (CD19/10) formats was used to assess lymphoblasts; CD34/13 was used to assess myeloblasts; and CD11b, CD13, CD16, and CD38 were used to assess abnormalities in myelopoiesis. Results Among the 17 BM samples submitted for cytopenia or MDS evaluation that had <5% blasts, 7 (41%) had immunophenotypic myeloid maturation abnormalities. Ten (59%) of the 17 cases had at least one myeloid-associated somatic mutation, with TET2 and ASXL1being the most commonly mutated genes. The ratio of myeloblasts to B-lymphoblasts, calculated using either CD10 or CD19, was >10:1 in 10/17 (59%) cases. Nine of the 17 (53%) cases had virtually no precursor B cells detected. Discrete abnormalities in more mature myeloid forms were seen in 7/10 (70%) cases with low numbers of B-lymphoblasts but in none of the 7 cases with significant numbers of B-lymphoblasts. MDS-associated mutations were more common in cases with rare B-lymphoblasts (7/9) than in those with higher percentages of precursor B cells (3/8), but the difference did not reach statistical significance (P = 0.15). Genes mutated in the group with B-lymphoblasts present included ASXL1 (3 cases), DNMT3A (2), TET2 (1) and TP53 (2). Two of these mutated cases presented with isolated thrombocytopenia. By comparison, myeloblast/lymphoblast ratios were >50:1 in all 10 unequivocal MDS/AML samples (>5% blasts); 8 (80%) of these cases had MDS-associated mutations, and 4 (50%) had mutations in multiple genes. Conclusions Decreases in BM precursor B cells in cases of possible low-grade MDS were usually, but not always, associated with the presence of MDS-associated mutations. However, cases with normal or increased precursor B cell numbers also showed MDS-associated mutations although immunophenotypic evidence of myeloid maturation abnormalities was not seen in this group. The identification of a subgroup of cytopenic patients with likely pathogenic mutations in bone marrow precursors but minimal phenotypic evidence of myeloid dysplasia may indicate clonal abnormalities primarily located outside the granulocyte or common stem precursor populations, e.g. restricted to the megakaryocytic lineage. Therefore, the presence of intact precursor lymphoblast and myeloid maturation by higher-dimensional flow cytometry as a primary criterion to argue against a diagnosis of low-grade MDS needs further evaluation, especially when granulocytopenia is absent. Disclosures: No relevant conflicts of interest to declare.
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Goldmacher, V. S., N. L. Tinnel, and B. C. Nelson. "Evidence that pinocytosis in lymphoid cells has a low capacity." Journal of Cell Biology 102, no. 4 (April 1, 1986): 1312–19. http://dx.doi.org/10.1083/jcb.102.4.1312.
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In contrast to adherent cells, human B and T lymphoblasts, marmoset monkey T lymphoblasts, and mouse T lymphoblasts do not form monolayers and have a poor ability to pinocytose. After a 10-min incubation of lymphoblasts at 37 degrees C, the level of internalized medium reached a plateau. During this time, lymphoblasts pinocytosed 3-4 femtoliters (1 fl = 10(-15) l) of medium per cell as calculated by the quantity of the entrapped pinocytic marker 5(6)-carboxyfluorescein. The levels of pinocytosed liquid did not increase during a subsequent 90-min incubation of cells at 37 degrees C. Adherent HeLa cells took up 27 fl of medium per cell per hour. Other types of adherent cells were reported by others to pinocytose 20 to 90 fl of medium per cell per hour. The process of pinocytosis in lymphoblasts appeared to be reversible since cells which were pre-loaded with carboxyfluorescein and then incubated at 37 degrees C in fresh medium lost the marker almost completely within 40 min. Similar results were obtained with horseradish peroxidase as the pinocytic marker. Further evidence that lymphoblasts have a low capacity for pinocytic internalization relative to adherent cells was obtained from the observation that Namalwa lymphoblasts were approximately 100 times more resistant to the cytotoxic action of the protein toxin gelonin than the adherent HeLa cells. Gelonin is a ribosome-inactivating toxin which is not capable of binding to cells, and its only mode for internalization appears to be pinocytosis. Ribosomes in cell lysates of the two lines were equally sensitive to gelonin. It is speculated that the poor pinocytic ability of lymphoid cells may reflect a fundamental difference between adherent and non-adherent cells and that this may impede the targeting of drugs into lymphoid cells.
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Schwartz, Marc Saul, Deepa Jeyakumar, Lloyd Earl Damon, Gary J. Schiller, and Matthew Joseph Wieduwilt. "A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS7064. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps7064.
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TPS7064 Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with < 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2nd- or 3rd-generation TKI or be TKI intolerant, > 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.
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Veszprémi, Anikó, Éva Katona, Csongor Kiss, György Vereb, László Muszbek, Flóra Kiss, Zsuzsanna Hevessy, and János Kappelmayer. "Leukemic lymphoblasts, a novel expression site of coagulation factor XIII subunit A." Thrombosis and Haemostasis 96, no. 08 (2006): 176–82. http://dx.doi.org/10.1160/th06-05-0270.
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SummaryBlood coagulation factor XIII (FXIII) is a protransglutaminase circulating asa tetramer formed by two types of subunits (A2B2). The intracellular dimeric form of FXIII (A2) is present in platelets, megakaryocytes, monocytes and macrophages and has been detected in mono-and megakaryocytic leukemias. The aim of our study was to investigate FXIII-A expression in newly diagnosed B cell acute lymphoblastic leukemia (ALL) samples. We examined 47 de novo ALL cases of B cell origin by triple color labeling with flow cytometry. FXIII-A was detected by a FITC conjugated monoclonal antibody combined with CD34 and CD45 staining. In selected cases FXIII-A was investigated on slides prepared from blasts and visualized with a fluorescent microscope. In addition, blasts were studied by Western blot analysis and FXIII-A was measured by a highly sensitive ELISA method. By flow cytometry 19 samples of the 47 cases were found to be FXIII-A positive. Antigen concentration was 3.11± 1.19 fg/blast, while normal lymphoid precursors and mature lymphocytes from B-CLL did not contain FXIII-A. In the lysate of lymphoblasts that were positive by flow cytometry, a single band (82 kDa) corresponding to FXIII-A was detected on Western blots. Confocal laser scanning microscopic examination revealed the presence of FXIII-A in the cytoplasm of these lymphoblasts. This novel expression site of FXIII-A in leukemic lymphoblasts can be utilized as a diagnostic tool and may also gain functional significance in B-lineage ALL.
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Manabe, A., KG Murti, E. Coustan-Smith, M. Kumagai, FG Behm, SC Raimondi, and D. Campana. "Adhesion-dependent survival of normal and leukemic human B lymphoblasts on bone marrow stromal cells." Blood 83, no. 3 (February 1, 1994): 758–66. http://dx.doi.org/10.1182/blood.v83.3.758.758.
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Abstract We investigated the requirement for intimate contact between bone marrow stroma and B lymphoblasts from normal donors and children with leukemia. By scanning electron microscopy, both normal and leukemic cells seeded onto stroma were surrounded by folds of stromal cells or were linked to the stroma by fine tendrils and uropods. Separation of normal B progenitors from stroma by use of microporous membranes led to significantly lower cell recoveries compared with results when contact was unimpeded. For instance, 22.5% +/- 1.8% (mean +/-SEM) of CD19+, CD34+ cells (most immature subset) were recovered after a 7-day culture directly on stroma, compared with 5.2%+/-0.7% after growth on membranes (P < .001 by Student's t test). In 6 of 11 cases of B-lineage acute lymphoblastic leukemia, separation of progenitors from stroma resulted in apoptosis and a greater than 60% reduction in cell recovery. In the remaining 5 cases, however, this effect was much less pronounced, with reductions in cell recoveries ranging from 48.5% to less than 1% (median, 39.0%) of control values. Inhibition of very late antigen-4, a surface molecule critical for adhesion of B lymphoblasts to stroma, was associated with a greater loss of normal CD34+ B progenitors compared with that for equivalent leukemic cells. These results establish direct contact with stroma as a survival requirement of normal B lymphoblasts and show marked heterogeneity in stromal dependency among B-lineage leukemic cells.
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Manabe, A., KG Murti, E. Coustan-Smith, M. Kumagai, FG Behm, SC Raimondi, and D. Campana. "Adhesion-dependent survival of normal and leukemic human B lymphoblasts on bone marrow stromal cells." Blood 83, no. 3 (February 1, 1994): 758–66. http://dx.doi.org/10.1182/blood.v83.3.758.bloodjournal833758.
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We investigated the requirement for intimate contact between bone marrow stroma and B lymphoblasts from normal donors and children with leukemia. By scanning electron microscopy, both normal and leukemic cells seeded onto stroma were surrounded by folds of stromal cells or were linked to the stroma by fine tendrils and uropods. Separation of normal B progenitors from stroma by use of microporous membranes led to significantly lower cell recoveries compared with results when contact was unimpeded. For instance, 22.5% +/- 1.8% (mean +/-SEM) of CD19+, CD34+ cells (most immature subset) were recovered after a 7-day culture directly on stroma, compared with 5.2%+/-0.7% after growth on membranes (P < .001 by Student's t test). In 6 of 11 cases of B-lineage acute lymphoblastic leukemia, separation of progenitors from stroma resulted in apoptosis and a greater than 60% reduction in cell recovery. In the remaining 5 cases, however, this effect was much less pronounced, with reductions in cell recoveries ranging from 48.5% to less than 1% (median, 39.0%) of control values. Inhibition of very late antigen-4, a surface molecule critical for adhesion of B lymphoblasts to stroma, was associated with a greater loss of normal CD34+ B progenitors compared with that for equivalent leukemic cells. These results establish direct contact with stroma as a survival requirement of normal B lymphoblasts and show marked heterogeneity in stromal dependency among B-lineage leukemic cells.
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Srivannaboon, Kleebsabai, Armen B. Shanafelt, Elisabetta Todisco, Carla P. Forte, Frederick G. Behm, Susana C. Raimondi, Ching-Hon Pui, and Dario Campana. "Interleukin-4 variant (BAY 36-1677) selectively induces apoptosis in acute lymphoblastic leukemia cells." Blood 97, no. 3 (February 1, 2001): 752–58. http://dx.doi.org/10.1182/blood.v97.3.752.
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Abstract Interleukin 4 (IL-4) suppresses the growth of acute lymphoblastic leukemia (ALL) cells, but its clinical usefulness is limited by proinflammatory activity due mainly to the interaction of cytokine with endothelial cells and fibroblasts. Stroma-supported cultures of leukemic lymphoblasts were used to test the antileukemic activity of an IL-4 variant, BAY 36-1677, in which the mutations Arg 121 to Glu and Thr 13 to Asp ensure high affinity for IL-4Rα/IL-2Rγ receptors expressed by lymphoid cells, without activation of the IL-4Rα/IL-13Rα receptors mainly expressed by other cells. BAY 36-1677 (25 ng/mL) was cytotoxic in 14 of 16 cases of B-lineage ALL; the median reduction in cell recovery after 7 days of culture was 85% (range, 17%-95%) compared to results of parallel cultures not exposed to the cytokine. Twelve of the 14 sensitive cases had t(9;22) or 11q23 abnormalities; 3 were obtained at relapse. BAY 36-1677 induced apoptosis in leukemic lymphoblasts but did not substantially affect the growth of normal CD34+ cells, thus conferring a growth advantage to normal hematopoietic cells over leukemic lymphoblasts in vitro. BAY 36-1677 had antileukemic activity equal or superior to that produced by native IL-4, but it lacked any effects on the growth of endothelial cells and fibroblasts. The molecular manipulation of IL-4 to abrogate its proinflammatory activity has generated a novel and therapeutically promising cytokine for the treatment of high-risk ALL.
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Frishman-Levy, Liron, Avishai Shemesh, Allan Bar-Sinai, Chao Ma, Zhenya Ni, Shahar Frenkel, Vera Muench, et al. "Central nervous system acute lymphoblastic leukemia: role of natural killer cells." Blood 125, no. 22 (May 28, 2015): 3420–31. http://dx.doi.org/10.1182/blood-2014-08-595108.
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Li, Yan, Rui Zhu, Lei Mi, Yihui Cao, and Di Yao. "Segmentation of White Blood Cell from Acute Lymphoblastic Leukemia Images Using Dual-Threshold Method." Computational and Mathematical Methods in Medicine 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/9514707.
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We propose a dual-threshold method based on a strategic combination of RGB and HSV color space for white blood cell (WBC) segmentation. The proposed method consists of three main parts: preprocessing, threshold segmentation, and postprocessing. In the preprocessing part, we get two images for further processing: one contrast-stretched gray image and one H component image from transformed HSV color space. In the threshold segmentation part, a dual-threshold method is proposed for improving the conventional single-threshold approaches and a golden section search method is used for determining the optimal thresholds. For the postprocessing part, mathematical morphology and median filtering are utilized to denoise and remove incomplete WBCs. The proposed method was tested in segmenting the lymphoblasts on a public Acute Lymphoblastic Leukemia (ALL) image dataset. The results show that the performance of the proposed method is better than single-threshold approach independently performed in RGB and HSV color space and the overall single WBC segmentation accuracy reaches 97.85%, showing a good prospect in subsequent lymphoblast classification and ALL diagnosis.