Asynchronous expression in B lineage acute lymphoblastic leukemia

Johns Hopkins Oncology Center, Pediatric Oncology, Baltimore, MD 21205.
Blood (Impact Factor: 10.45). 08/1988; 72(1):299-307.
Source: PubMed

ABSTRACT Cell surface phenotypes of 113 B lineage acute lymphocytic leukemia (ALL) cases, defined by the presence of HLA-DR and at least one B-cell-specific antigen (either CD19, CD20, or CD22), were compared with antigen-defined stages of normal B lymphocyte development. The cases were first evaluated for expression of HLA-DR, CD19, CD34, CD10, CD20, and CD22 by indirect one-color immunofluorescence. Pairwise comparisons of cell surface marker expression were performed for each leukemic sample: no correlations were observed for paired antigen expression on the leukemic samples using antigens expressed either early or late during normal B lymphoid development. Complete immunophenotypes of the cases were then compared with normal B-cell developmental stages. Sixteen different complete immunophenotypes were observed on the leukemias that were not found in normal marrow; at least 78% of the cases demonstrated such "asynchronous" combinations of B lymphoid-associated differentiation antigens. Several samples were subsequently studied by two-color immunofluorescence, and the presence of doubly labeled cells with "asynchronous" antigen combinations was confirmed. These results indicate that the majority of B lineage leukemias exhibit "developmental asynchrony," as compared with normal marrow B cells. The data further suggest that ALL cases do not accurately represent cells arrested at the stage where the leukemogenic event occurred. Rather, ALL appears to be a disease in which there may be maturation of leukemic blasts; but this maturation is "asynchronous" when compared with the normal developmental process.

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Available from: Judith E Karp, Nov 23, 2014
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    • "Therefore the strategy for MRD detection in B-ALL is less straightforward than T-ALL. The use of PB for the detection of MRD is debatable because subtle leukaemia-associated deregulation of gene expression extends to many other molecules normally expressed during B-cell differentiation [33,34]. However two studies [35,36] have shown that paired MRD values in BM and PB are highly concordant in T-ALL. "
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    ABSTRACT: Over expression of 9-O-acetylated sialoglycoproteins (Neu5,9Ac2-GPs, abbreviated as OAcSGP) has been demonstrated as a disease-associated antigen on the lymphoblasts of childhood acute lymphoblastic leukaemia (ALL). Achatinin-H, a lectin, has selective affinity towards terminal 9-O-acetylated sialic acids-alpha2-6-Nacetylated galactosamine. Exploring this affinity, enhanced expression of OAcSGP was observed, at the onset of disease, followed by its decrease with chemotherapy and reappearance with relapse. In spite of treatment, patients retain the diseased cells referred to as minimal residual disease (MRD) responsible for relapse. Our aim was to select a suitable template by using the differential expression of OAcSGP along with other known CD antigens to monitor MRD in peripheral blood (PB) and bone marrow (BM) of Indian patients with B- or T-ALL during treatment and correlate it with the disease status. A two-year longitudinal follow-up study was done with 109 patients from the onset of the disease till the end of chemotherapy, treated under MCP841protocol. Paired samples of PB (n = 1667) and BM (n = 999) were monitored by flow cytometry. Three templates selected for this investigation were OAcSGP+CD10+CD19+ or OAcSGP+CD34+CD19+ for B-ALL and OAcSGP+CD7+CD3+ for T-ALL. Using each template the level of MRD detection reached 0.01% for a patient in clinical remission (CR). 81.65% of the patients were in CR during these two years while the remaining relapsed. Failure in early clearance of lymphoblasts, as indicated by higher MRD, implied an elevated risk of relapse. Soaring MRD during the chemotherapeutic regimen predicted clinical relapse, at least a month before medical manifestation. Irrespective of B- or T-lineage ALL, the MRD in PB and BM correlated well. A range of MRD values can be predicted for the patients in CR, irrespective of their lineage, being 0.03 +/- 0.01% (PB) and 0.05 +/- 0.015% (BM). These patients may not be stated as normal with respect to the presence of MRD. Hence, MRD study beyond two-years follow-up is necessary to investigate further reduction in MRD, thereby ensuring their disease-free survival. Therefore, we suggest use of these templates for MRD detection, during and post-chemotherapy for proper patient management strategies, thereby helping in personalizing the treatment.
    BMC Cancer 02/2008; 8(1):40. DOI:10.1186/1471-2407-8-40 · 3.36 Impact Factor
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    • "More recently, expression of characteristic myeloid antigens has been associated with distinct genetically defined subgroups (Borowitz et al, 1991; Griesinger et al, 1994; Lenkei et al, 1991; Ludwig et al, 1993, 1994). Other leukaemiaassociated immunophenotypes include asynchronous expression of maturational stage-associated antigens in Blineage ALL (Hurwitz et al, 1989), ectopic expressions of antigens in T-lineage ALL (van Dongen et al, 1993; Campana et al, 1991), aberrant antigen expression of B-and T-lineage associated antigens in leukaemic samples of the respective other lymphoid lineage (Grü mayer et al, 1991; Uckun et al, 1989; Muraguchi et al, 1992), and loss or low expression of common surface antigens such as CD45 in B-lineage ALL (Behm et al, 1992). Besides the pretherapeutic characterization of ALL, aberrant and asynchronous antigen expression may potentially be used for detection of persistent cells with LAIP in haematological complete remission (CR), termed minimal residual disease (MRD). "
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    ABSTRACT: Analysis of differentiation antigens on leukaemic blasts is routinely done for diagnostic purposes, i.e. determination of stage of differentiation and lineage assignment. Acute lymphoblastic leukaemias are also frequently characterized by a leukaemia-associated immunophenotype (LAIP), either the coexpression of differentiation antigens physiologically restricted to other stages of differentiation (asynchronous LAIP) or cell lineages (aberrant LAIP). We defined LAIP in 241 consecutive unselected B-lineage (n = 193) and T-lineage (n = 48) ALL by three-colour flow cytometry using directly conjugated monoclonal antibodies. The incidence of LAIP was found to be 91.7%. In 63% of patients two to six leukaemia-associated expression patterns were detected. In order to study the specificity of LAIP in a therapy-relevant setting, remission bone marrow samples from patients with B-lineage ALL were analysed for the expression of T-lineage-associated phenotypes on the normal bone marrow cells and vice versa. The frequency of all T-lineage LAIP+ cells and all aberrant B-lineage LAIP+ cells was <1% in regenerating bone marrow samples at different timepoints. The incidence and clinical significance of LAIP+ cells was studied in 196 remission marrows of 70 ALL patients (55 remaining in CCR, 14 with bone marrow relapse, one with isolated CNS relapse). The presence of >1% LAIP+ at two consecutive timepoints predicted 5/8 bone marrow relapses in B-lineage ALL. The occurrence of LAIP+ cells >1% in T-lineage ALL after induction therapy predicted relapse in 7/7 cases. In conclusion, flow cytometric detection of LAIP+ cells appears to be a powerful tool for the prediction of outcome in ALL.
    British Journal of Haematology 03/1999; 105(1):241 - 255. DOI:10.1111/j.1365-2141.1999.01300.x · 4.71 Impact Factor
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    ABSTRACT: The clinical utility of early response measures Approximately 80% of children with acute lymphoblastic leukemia (ALL) are cured with contemporary risk-directed treatment, with therapies of different intensities administered to patient groups with differential risks of relapse. Many different clinical and biological features are used to identify different risk groups. Early response to therapy, defined as the initial degree and rate of disease regression prior to end induction, is one of the most powerful. Simple enumeration of blasts remaining in peripheral blood (PB) or bone marrow (BM) at defined times during induction therapy is highly predictive of treatment outcome among large groups of patients with ALL.(1) The Berlin-Frankfurt-Munster (BFM) group showed in ALL-BFM 83 that the number of blasts remaining in the peripheral blood following seven days treatment with prednisone and a single dose of intrathecal methotrexate separates patients into two subgroups with divergent outcomes.(2) Prednisone good responders (PGR) consist of the approximately 90% of patients that have < 1000 blasts/ml remaining in the PB and have an excellent outcome. In contrast, prednisone poor responders (PPR) that have = 1000 blasts/
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