Detection of Minimal Residual Acute Lymphoblastic Leukemia by Immunological Marker Analysis: Possibilities and Limitations

Dongen, Jacques J.M. van; Hooijkaas, Herbert; Adriaansen, H. J.; Hählen, K.; Zanen, G E van

doi:10.1007/978-94-009-4273-8_11

Cited by 66 publications

(102 citation statements)

References 74 publications

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“…This can be performed via flow cytometric detection of aberrant or unusual immunophenotypes or via PCR-based detection of leukemia-specific sequences, such as junctional regions of Ig and TCR rearrangements or fusion regions of chromosomal aberrations. 44,45 The combined immunophenotypic and immunogenotypic features of TCR␥␦ + T-ALL as identified in this study, provide numerous patient-specific targets that can be employed for flow cytometric or PCR-based MRD detection. Flow cytometric MRD detection can be based on double or triple labelings using TdT in combination with one or two T cell markers or V␥ and V␦ expression.…”

Section: Tablementioning

confidence: 91%

Immunophenotypic and immunogenotypic characteristics of TCRγδ+ T cell acute lymphoblastic leukemia

et al. 1999

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Section: Tablementioning

confidence: 91%

Immunophenotypic and immunogenotypic characteristics of TCRγδ+ T cell acute lymphoblastic leukemia

et al. 1999

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“…[17][18][19][20] Sensitivities of around 5% are clinically relevant for initial diagnosis, but they are certainly not sufficient for detection of minimal residual disease (MRD) in ALL patients which requires sensitivities of 10 −4 to 10 −5 . 35 It has been suggested that sensitivities of 10 −2 to 10 −3 as determined by PCR might be predictive for slow remission upon chemotherapy, 36 but such sensitivities cannot easily be reached via heteroduplex analysis of PCR products, unless most of the polyclonal T cells are depleted before DNA or RNA extraction. Nevertheless, heteroduplex PCR analysis of TCR gene rearrangements is sufficiently sensitive for monitoring patients with chronic T cell leukemias as well as patients with oligoclonal T cell proliferations in order to predict the possible outgrowth of a dominant cell population.…”

Section: Figurementioning

confidence: 99%

Heteroduplex PCR analysis of rearranged T cell receptor genes for clonality assessment in suspect T cell proliferations

et al. 1997

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Molecular analysis of T cell receptor (TCR) genes is frequently used to prove or exclude clonality and thereby support the diagnosis of suspect T cell proliferations. PCR techniques are more and more being used for molecular clonality studies. The main disadvantage of the PCR-based detection of clonal TCR gene rearrangements, is the risk of false-positive results due to 'background' amplification of similar rearrangements in polyclonal reactive T lymphocytes. Therefore, PCR-based clonality assessment should include analyses that discern between PCR products derived from monoclonal and polyclonal cell populations. One such method is heteroduplex analysis, in which homo-and heteroduplexes resulting from denaturation (at 94°C) and renaturation (at lower temperatures) of PCR products, are separated in non-denaturing polyacrylamide gels based on their conformation. After denaturation/renaturation, PCR products of clonally rearranged TCR genes give rise to homoduplexes, whereas in case of polyclonal cells heteroduplexes with heterogeneous junctions are formed. We studied heteroduplex PCR analysis of TCR gene rearrangements with respect to the time and temperature of renaturation and the size of the PCR products. Variation in time did not have much influence, but higher renaturation temperatures (Ͼ30°C) clearly showed better duplex formation. Nevertheless, distinction between monoclonal and polyclonal samples was found to be more reliable at a renaturation temperature of 4°C, using relatively short PCR products. To determine the sensitivity of heteroduplex analysis with renaturation at 4°C, (c)DNA of T cell malignancies with proven clonal rearrangements was serially diluted in (c)DNA of polyclonal mononuclear peripheral blood cells and amplified using V and C primers (TCRB genes) or V and J primers (TCRG and TCRD genes). Clonal TCRB and TCRD gene rearrangements could be detected with a sensitivity of at least 5%, whereas the sensitivity for TCRG genes was somewhat lower (10-15%). The latter could be improved by use of V␥ member primers instead of V␥ family primers. We conclude from our results that heteroduplex PCR analysis of TCR gene rearrangements is a simple, rapid and cheap alternative to Southern blot analysis for detection of clonally rearranged TCR genes.

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“…12 Another proviso is that a proportion of patients have leukaemic blasts which do not obey the ontogenic rules and disclose aberrant or asynchronous expression of antigens. 13,14 This has been a particular problem as it has been recognised that the so-called myeloid antigens CD13 and 33 may be present on ALL blasts. [15][16][17] The literature suggests that the incidence of CD13 and/or CD33 positivity is in the order of 5-10% in children and in up to 20% of adult cases.…”

Section: Figurementioning

confidence: 99%

Analysis of the immunophenotype of children treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia Trial XI (MRC UKALLXI)

Hann

Richards²,

Eden

et al. 1998

Leukemia

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Despite many years of meticulous immunophenotyping of childhood acute lymphoblastic leukaemia (ALL) cases the prognostic significance of some subtypes remains unclear. The Medical Research Council UKALLXI trial (1990)(1991)(1992)(1993)(1994)(1995)(1996) in which uniform treatment has been given to 2090 children with ALL below the age of 18 years and above the age of 1 year, has afforded the opportunity to review these issues. Children with ALL of mature B cell type were not entered into this trial. Immunophenotype analysis was performed in each individual trial centre, but results were centrally reviewed in all cases, and were both available and considered adequate in 1934 (93%) of the first 2090 patients entered. The main diagnostic categories were early pre-B or null reported in 60 cases (3.1%), common ALL in 1242 (64.2%), pre-B in 252 (13.0%), 'common' or pre-B in 172 (8.9%) and T cell in 207 (10.7%) cases. Children with T cell disease were significantly more likely to be over the age of 10 years, with central nervous system disease at diagnosis and to be CD34 negative. They also had a higher incidence of high white cell count and were more likely to be of the FrenchAmerican-British (FAB) L2 morphological subtype. Patients with 'null' cell disease tended to be less than 2 years or greater than 10 years of age, and CD13 and CD33 positive. CD10 was associated with lower white cell count (WBC) at diagnosis, younger age and FAB L1 morphological subtype. The presence of cytoplasmic immunoglobulin in pre-B cells was not associated with any specific clinical or laboratory features. CD34 positivity was less common in T cell patients and was associated with low WBC. Disease-free survival (DFS) and 95% confidence intervals (CI) at 5 years from diagnosis was 52% (95% CI: 44-59%) for T cell disease, 58% (95% CI: 43-73%) for early pre-B (or null cell) disease and 65% (95% CI: 62-68%) for common or pre-B disease; there being no significant difference between common and pre-B disease with regard to disease outcome. Patients with T cell disease had a worse prognosis than any other immunophenotype group (P Ͻ 0.00005). However this worse outcome was no longer significant after allowing for the other principal prognostic factors of age, gender and white cell count at diagnosis except for the very small number with WBC Ͻ20 × 10 9 /l and T cell disease. Those with CD10-positive leukaemia did better than those who were CD10 negative (P Ͻ 0.00005), with DFS at 5 years 64% (95% CI: 62-67%) for positive vs 56% (95% CI: 49-62%) for CD10 negative. CD10 positivity did not have independent significance when white count, gender and age were taken into account. CD13, CD33, and cytoplasmic positivity carried no prognostic significance. Keywords: immunophenotype; prognosis; acute lymphoblastic leukaemia (ALL); children IntroductionImmunological heterogeneity of ALL has been recognised for many years. ing which time the use of standardised panels of antibodies has permitted allocation of more than 98% of leukaemias to their respective lineage...

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Detection of Minimal Residual Acute Lymphoblastic Leukemia by Immunological Marker Analysis: Possibilities and Limitations

Cited by 66 publications

References 74 publications

Immunophenotypic and immunogenotypic characteristics of TCRγδ+ T cell acute lymphoblastic leukemia

Immunophenotypic and immunogenotypic characteristics of TCRγδ+ T cell acute lymphoblastic leukemia

Heteroduplex PCR analysis of rearranged T cell receptor genes for clonality assessment in suspect T cell proliferations

Analysis of the immunophenotype of children treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia Trial XI (MRC UKALLXI)

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