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20. Expression of T Cell Receptor Associated Proteins During Human T Cell Development

Author

Campana, D., Coustan-Smith, E., Wong, L., Janossy, G., Melchers, Fritz, editor, Albert, E. D., editor, von Boehmer, H., editor, Dierich, M. P., editor, Du Pasquier, L., editor, Eichmann, K., editor, Gemsa, D., editor, Götze, O., editor, Kalden, J. R., editor, Kaufmann, S. H. E., editor, Kirchner, H., editor, Resch, K., editor, Riethmüller, G., editor, Schimpl, A., editor, Sorg, C., editor, Steinmetz, M., editor, Wagner, H., editor, and Zachau, H. G., editor

Published
1989
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21. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy

Author

Pui, C-H, primary, Pei, D, additional, Raimondi, S C, additional, Coustan-Smith, E, additional, Jeha, S, additional, Cheng, C, additional, Bowman, W P, additional, Sandlund, J T, additional, Ribeiro, R C, additional, Rubnitz, J E, additional, Inaba, H, additional, Gruber, T A, additional, Leung, W H, additional, Yang, J J, additional, Downing, J R, additional, Evans, W E, additional, Relling, M V, additional, and Campana, D, additional

Published
2016
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22. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels.

Author

Mullighan, C.G., Jeha, S., Pei, D., Payne-Turner, D., Coustan-Smith, E., Roberts, K.G., Waanders, E., Choi, J.K., Ma, X., Raimondi, S.C., Fan, Y., Yang, W, Song, G., Yang, J.J., Inaba, H., Downing, J.R., Leung, W.H., Bowman, W.P., Relling, M.V., Evans, W.E., Zhang, J., Campana, D., Pui, C.H., Mullighan, C.G., Jeha, S., Pei, D., Payne-Turner, D., Coustan-Smith, E., Roberts, K.G., Waanders, E., Choi, J.K., Ma, X., Raimondi, S.C., Fan, Y., Yang, W, Song, G., Yang, J.J., Inaba, H., Downing, J.R., Leung, W.H., Bowman, W.P., Relling, M.V., Evans, W.E., Zhang, J., Campana, D., and Pui, C.H.

Abstract

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Published
2015

23. Characterization of CD34+, CD13+, CD33- cells, a rare subset of immature human hematopoietic cells

Author

Gaipa, G, Coustan Smith, E, Todisco, E, Maglia, O, Biondi, A, Campana, D., Gaipa, G, Coustan Smith, E, Todisco, E, Maglia, O, Biondi, A, and Campana, D

Subjects
Adult, Adolescent, flow cytometry, Sialic Acid Binding Ig-like Lectin 3, Antigens, Differentiation, Myelomonocytic, Infant, Antigens, CD34, Bone Marrow Cells, Cell Differentiation, leukemic myeloblasts, CD13 Antigens, Middle Aged, Fetal Blood, Hematopoietic Stem Cells, Immunophenotyping, Antigens, CD, hematopoiesi, Child, Preschool, minimal residual disease, Humans, Cell Lineage, Myeloid Cells, CD34(+) cell, Child
Abstract

Background and Objectives. Hematopoietic progenitor cells that express CD34 are heterogeneous in their lineage affiliation and degree of maturation. Expression of CD13 and CD33 antigens indicates myeloid lineage association, but the precise sequence of expression of these two markers during differentiation is unclear. We noted the presence of CD34(+) cells expressing CD13 but lacking CD33, a subset of cells not yet well characterized. In this report we describe the prevalence and the immunophenotype of this cell subset. Design and Methods. We studied the immunophenotype of immature myeloid cells in human bone marrow samples from 11 healthy transplantation donors and in 4 cord blood samples. We used four-color flow cytometry and a large panel of monoclonal antibodies directed against lineage and differentiation-associated antigens. Three additional bone marrow samples were analyzed after immunomagnetic sorting of 034 cells. We focused our analysis on the subset of cells defined by the expression of CD34 and CD13 and the lack of CD33. Results. We found CD34(+), CD13(+), CD33(-) cells in all 11 bone marrow and 4 cord blood samples studied. These cells represented 0.5+/-0.5% (mean +/- SD) and 0.8+/-1.2% of mononucleated cells, respectively. CD34(+), CD13(+), CD33(-) cells appeared to be more immature than those expressing CD33 because of their light scatter characteristics (smaller size and lower granularity), the expression of markers associated with early hematopoietic cells (CD90, CD133 and CD117), and the absence of lineage-associated markers. Interpretation and Conclusions. These findings suggest that the expression of CD13 precedes that of CD33 during myeloid differentiation, and that CD34(+), CD13(+), CD33(-) cells are at an early stage of human myeloid cell differentiation. (C)2002, Ferrata Storti Foundation.

Published
2002

24. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

Author

Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, and Loh

Published
2012

26. Mutations In Ig Alpha (Cd79A) Result In In B-Cell Development

Author

Minegishi, Y, Coustan-Smith, E, Rapalus, L, Ersoy, F, Campana, D, Conley, ME, and Çocuk Sağlığı ve Hastalıkları

Subjects
hemic and lymphatic diseases, Research & Experimental Medicine
Abstract

Mutations in Btk, mu heavy chain, or the surrogate light chain account for 85-90% of patients with early onset hypogammaglobulinemia and absent B cells. The nature of the defect in the remaining patients is unknown. We screened 25 such patients for mutations in genes encoding components of the pre-B-cell receptor (pre-BCR) complex. A 2-year-old girl was found to have a homozygous splice defect in Ig alpha, a transmembrane protein that forms part of the Ig alpha/Ig beta signal-transduction module of the pre-BCR. Studies in mice suggest that the Ig beta component of the pre-BCR influences V-DJ rearrangement before cell-surface expression of mu heavy chain. To determine whether Ig alpha plays a similar role, we compared B-cell development in an Ig alpha-deficient patient with that seen in a mu heavy chain-deficient patient. By immunofluorescence, both patients had a complete block in B-cell development at the pro-B to pre-B transition; both patients also had an equivalent number and diversity of rearranged V-DJ sequences. These results indicate that mutations in Ig alpha can be a cause of agammaglobulinemia. Furthermore, they suggest that Ig alpha does not play a critical role in B-cell development until it is expressed, along with mu heavy chain, as part of the pre-BCR.

Published
1999

27. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia

Author

Coustan Smith, E, Mullighan, C, Onciu, M, Behm, F, Raimondi, S, Pei, D, Cheng, C, Su, X, Rubnitz, J, Basso, G, Biondi, A, Pui, C, Downing, J, Campana, D, Mullighan, CG, Behm, FG, Raimondi, SC, Rubnitz, JE, Pui, CH, Downing, JR, Campana, D., BIONDI, ANDREA, Coustan Smith, E, Mullighan, C, Onciu, M, Behm, F, Raimondi, S, Pei, D, Cheng, C, Su, X, Rubnitz, J, Basso, G, Biondi, A, Pui, C, Downing, J, Campana, D, Mullighan, CG, Behm, FG, Raimondi, SC, Rubnitz, JE, Pui, CH, Downing, JR, Campana, D., and BIONDI, ANDREA

Abstract

Background: About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. Methods: Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. Findings: 30 patients (12·6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a-, CD8-, CD5weak with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial). Interpretation: ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management

Published
2009

28. IL-2 adenovector-transduced autologous tumor cells induce antitumor immune responses in patients with neuroblastoma

Author

Bowman, L., Grossmann, M., Rill, D., Michael Brown, Zhong, W. -Y, Alexander, B., Leimig, T., Coustan-Smith, E., Campana, D., Jenkins, J., Woods, D., Kitchingman, G., Vanin, E., and Brenner, M.

Subjects
Adolescent, Immunology, Genetic Vectors, Infant, Cell Biology, Hematology, T-Lymphocytes, Helper-Inducer, Transfection, Biochemistry, Immunotherapy, Adoptive, Adenoviridae, Killer Cells, Natural, Neuroblastoma, T-Lymphocyte Subsets, Child, Preschool, Humans, Interleukin-2, Longitudinal Studies, Child, T-Lymphocytes, Cytotoxic
Abstract

In many different murine models, the immunogenicity of tumor cells can be increased by transduction with a range of immunostimulatory genes, inducing an immune response that causes regression of pre-existing unmodified tumor cells. To investigate the relevance of these animal models to pediatric malignancy, we used autologous unirradiated tumor cells transduced with an adenovirus-IL-2 to immunize 10 children with advanced neuroblastoma. In a dose-escalation study, we found that this tumor immunogen induced a moderate local inflammatory response consisting predominantly of CD4+ T lymphocytes, and a systemic response, with a rise in circulating CD25+and DR+ CD3+ T cells. Patients also made a specific antitumor response, manifest by an IgG antitumor antibody and increased cytotoxic T-cell killing of autologous tumor cells. Clinically, five patients had tumor responses after the tumor immunogen alone (one complete tumor response, one partial response, and three with stable disease). Four of these five patients were shown to have coexisting antitumor cytotoxic activity, as opposed to only one of the patients with nonresponsive disease. These results show a promising correlation between preclinical observations and clinical outcome in this disease, and support further exploration of the approach for malignant diseases of children. © 1998 by The American Society of Hematology.

Published
1998

29. ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy

Author

Bhojwani, D, primary, Pei, D, additional, Sandlund, J T, additional, Jeha, S, additional, Ribeiro, R C, additional, Rubnitz, J E, additional, Raimondi, S C, additional, Shurtleff, S, additional, Onciu, M, additional, Cheng, C, additional, Coustan-Smith, E, additional, Bowman, W P, additional, Howard, S C, additional, Metzger, M L, additional, Inaba, H, additional, Leung, W, additional, Evans, W E, additional, Campana, D, additional, Relling, M V, additional, and Pui, C-H, additional

Published
2011
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45. Analysis of signal transduction in B chronic lymphocytic leukemia cells

Author

Drexler, HG, Brenner, MK, Coustan-Smith, E, Gignac, SM, and Hoffbrand, AV

Abstract

We report here experiments on the analysis of cellular signal transduction in a series of patients with chronic B cell disorders (B cell chronic lymphocytic leukemia [B-CLL] and prolymphocytic leukemia). We compared the response of the leukemic cells with primary external signals (interleukin 2 [IL-2] or B cell differentiation factors [BCDF or IL-6]) with their response to secondary inducers (the phorbol ester (12–O-tetradecanoylphorbol-13-acetate [TPA] or the calcium ionophore A23187) that circumvent the first part of the signal transduction pathway by directly activating the key enzyme protein kinase C. One BCDF was synthesized by mitogen-activated peripheral blood B lymphocytes; a second BCDF was constitutively produced by the human bladder carcinoma cell line T24. Changes in morphology, Tac (IL-2 receptor) expression, RNA synthesis measured by 3H-uridine uptake, and immunoglobulin production tested by enzyme-linked immunosorbent assay were used as parameters of successful signal transduction. TPA alone and TPA plus A23187 (synergistically) effectively initiated differentiation in all the leukemia cases. Neither IL-2 nor BCDF (singly or in combinations) caused equivalent responses. On the other hand, IL-2 and BCDF produced a substantial differentiation effect on normal B lymphocytes. Our data suggest that (a) B-CLL cells are able to respond to direct stimulation of the second messenger pathway (through protein kinase C) but not to the physiological stimuli IL-2 or BCDF; (b) the defect in signal transduction appears to be located upstream of protein kinase C (a possible candidate is a G protein); (c) malignant B cells may spontaneously or after treatment with inducers express the IL- 2 receptor (Tac antigen) in the absence of a functional differentiating response to IL-2; and (d) signs of proliferation/differentiation in B- CLL samples after incubation with IL-2 or BCDF might be due to contamination of the cell populations with residual normal B cells.

Published
1988
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46. Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia

Author

Secker-Walker, LM, Cooke, HM, Browett, PJ, Shippey, CA, Norton, JD, Coustan-Smith, E, and Hoffbrand, AV

Abstract

Philadelphia (Ph1) chromosome breakpoints in acute lymphoblastic leukemia (ALL) are of two kinds: those within the breakpoint cluster region (bcr+), as in chronic myeloid leukemia (CML), and those outside it (bcr-). These encode different c-abl messenger RNAs (mRNAs), p210 and p190, respectively. It has been suggested that one class of Ph+ ALL (bcr+) may be a variant of CML arising in a multipotent stem cell, the other (bcr-) de novo ALL initiated in a lymphoid-committed progenitor. Thirty-two cases of ALL (12 Ph1+, ten chromosomally normal, and ten non- mitotic cases) were investigated for bcr involvement. Breakpoints were found within five Ph1+ and in one normal case. There was no difference in clinical features, common ALL antigen (CALLA) positivity, cytogenetics, or response to treatment between the 6 bcr+ and 7 Ph1+ bcr- patients. Myeloid antigen expression was found in 2 bcr+ cases. Bcr rearrangement appeared to be restricted to the lymphoblastic component of marrow or blood in at least four bcr+ cases. In one case, separated myeloid and lymphoid cell fractions were both bcr+. Potential heterogeneity of the Ph1+ target cell, as seen in this study, may be more important in determining disease outcome than the precise location of the Ph breakpoint.

Published
1988
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47. Synergistic action of calcium ionophore A23187 and phorbol ester TPA on B-chronic lymphocytic leukemia cells

Author

Drexler, HG, Brenner, MK, Coustan-Smith, E, Wickremasinghe, RG, and Hoffbrand, AV

Abstract

The peripheral blood mononuclear cells from 16 patients with B-chronic lymphocytic leukemia (B-CLL, n = 13), B-prolymphocytic leukemia (B-PLL, n = 2) or hairy cell leukemia (n = 1) were incubated in the presence of the phorbol ester 12–0-tetradecanoylphorbol-13-acetate (TPA) and the calcium ionophore A23187. A synergy between these inducers was found with respect to morphological changes and B cell proliferation and differentiation. A23187 used alone did not activate the cells. B-CLL cells treated with the double stimulus acquired a plasmacytoid morphology, showed significantly higher incorporation of 3H-thymidine and 3H-uridine, and produced significantly higher amounts of monoclonal immunoglobulin compared with the same cells exposed to either of the inducers alone. These results indicate that phorbol ester and calcium ionophore act synergistically on B-CLL cells to induce proliferation and differentiation. B-PLL cells responded more vigorously to the signals provided by TPA and A23187. Previous studies showed that TPA and A23187 can mimic the two physiological second messengers diacylglycerol and inositol trisphosphate in the transduction of signals leading to cell activation, proliferation, and differentiation in normal B cells. The present findings suggest that the capacity of B- CLL and B-PLL cells to differentiate in response to signals of the second messenger pathway is intact.

Published
1987
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48. Variable Philadelphia Breakpoints and Potential Lineage Restriction of her Rearrangement in Acute Lymphoblastic Leukemia

Author

Seeker-Walker, L.M., Cooke, H.M.G., Browett, P.J., Shippey, C.A., Norton, J.D., Coustan-Smith, E., and Hoffbrand, A.V.

Abstract

Philadelphia (Ph1) chromosome breakpoints in acute lymphoblastic leukemia (ALL) are of two kinds: those within the breakpoint cluster region (bcr+), as in chronic myeloid leukemia (CML), and those outside it (bcr−). These encode different c-ablmessenger RNAs (mRNAs), p210 and p190, respectively. It has been suggested that one class of Ph+ALL (bcr+) may be a variant of CML arising in a multipotent stem cell, the other (bcr−) de novo ALL initiated in a lymphoid-committed progenitor. Thirty-two cases of ALL (12 Ph1+, ten chromosomally normal, and ten non-mitotic cases) were investigated for bcr involvement. Breakpoints were found within five Ph1+and in one normal case. There was no difference in clinical features, common ALL antigen (CALLA) positivity, cytogenetics, or response to treatment between the 6 bcr+and 7 Ph1+bcr−patients. Myeloid antigen expression was found in 2 bcr+cases. Bcr rearrangement appeared to be restricted to the lymphoblastic component of marrow or blood in at least four bcr+cases. In one case, separated myeloid and lymphoid cell fractions were both bcr+. Potential heterogeneity of the Ph1+target cell, as seen in this study, may be more important in determining disease outcome than the precise location of the Ph breakpoint. © 1988 by Grune & Stratton, Inc.

Published
1988
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50. Methodological approach to minimal residual disease detection by flow cytometry in adult B-lineage acute lymphoblastic leukemia

Author

Krampera, M., Perbellini, O., Vincenzi, C., Zampieri, F., Pasini, A., Maria SCUPOLI, Guarini, A., Propris, M. S., Coustan-Smith, E., Vitale, A., Campana, D., Foà, R., and Pizzolo, G.

Subjects
Adult, b-lineage all, B-Lymphocytes, Neoplasm, Residual, MRD, flow-cytometry, B-lineage ALL, normal B-cell precursors, Antibodies, Monoclonal, Bone Marrow Cells, acute lymphoblastic leukemia, flow-cytometry, mrd, normal b-cell precursors, flow cytometry, minimal residual disease, Flow Cytometry, Burkitt Lymphoma, Antigens, CD, Reference Values, Humans, Regeneration, Child, Fluorescein-5-isothiocyanate
Abstract

A flow cytometric approach to minimal residual disease (MRD) monitoring useful in childhood B-lineage acute lymphoblastic leukemia (ALL) is discussed here in the context of ALL in adults. Of 64 leukemia samples analyzed, 95.3% had at least one abnormal phenotype (57.3% had two or more) as compared to physiologic B-cell precursors in adult bone marrow. The method was sensitive enough to detect one leukemic cell among 10,000 normal cells in 16/19 experiments (84.2%). Blast phenotypes were stable in culture and at relapse, and were useful for MRD monitoring in patients. Marker combinations for childhood ALL are also applicable to adult cases.

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