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At least 505 records · Page 28Linked to original sources
PubMed2001

Determination of myeloid antigen expression on childhood acute lymphoblastic leukaemia cells: discrepancies using different monoclonal antibody clones.

Prospective clinical studies including large numbers of patients have led to the conclusion that co-expression of myeloid antigens in childhood acute lymphoblastic leukaemia (My+ ALL) does not have prognostic significance. However, reports of the frequency of My+ ALL in children vary widely across laboratories using different mAb clones and staining and analysing procedures. Taking two commonly accepted thresholds of positivity for myeloid antigens (20 and 30%), we analysed the immunoreactivity of the most widely employed mAb clones against CD13 (SJ1D1, L138 and My7) and CD33 (My9, P67.6 and D3HL60) and compared the proportions of My+ ALL detected by these clones in childhood ALL. The correlation between myeloid antigen expression and the presence of the t(12;21) translocation was analysed concomitantly in the same samples. The percentage of ALL cases positive for myeloid markers varied significantly depending on the mAb clone and the positive threshold. Among patients with B-ALL, the proportion of CD13+ ALL was significantly lower using SJ1D1 than using L138 or My7, while the proportion of CD33+ ALL was significantly higher for My9 than for P67.6 or D3HL60. Analysis of the co-expression of CD13 and CD33 on B-ALL cells using combinations of mAb clones showed that this frequency was either underestimated by the SJ1D1/D3HL60 or overestimated by the L138/P67.6 and My7/My9 combinations. A correlation between CD13/CD33 positivity and the t(12;21) translocation was uniformly observed in B-ALL patients for a positive threshold of 30%, whereas SJ1D1/D3HL60 detected no correlation between t(12;21) and CD13/CD33 positivity when the threshold was lowered to 20%. These data show that the mAb clones commonly used to detect the CD13 and CD33 surface antigens have variable immunoreactivity against childhood ALL cells, which may partly explain the conflicting reports concerning the prognostic significance of myeloid antigen expression in paediatric ALL and its association with different translocations. The present findings may also be of clinical importance for therapeutic choices.

Antibodies, Monoclonal↗
PubMed2001

Determination of myeloid antigen expression on childhood acute lymphoblastic leukaemia cells: discrepancies using different monoclonal antibody clones.

Prospective clinical studies including large numbers of patients have led to the conclusion that co-expression of myeloid antigens in childhood acute lymphoblastic leukaemia (My+ ALL) does not have prognostic significance. However, reports of the frequency of My+ ALL in children vary widely across laboratories using different mAb clones and staining and analysing procedures. Taking two commonly accepted thresholds of positivity for myeloid antigens (20 and 30%), we analysed the immunoreactivity of the most widely employed mAb clones against CD13 (SJ1D1, L138 and My7) and CD33 (My9, P67.6 and D3HL60) and compared the proportions of My+ ALL detected by these clones in childhood ALL. The correlation between myeloid antigen expression and the presence of the t(12;21) translocation was analysed concomitantly in the same samples. The percentage of ALL cases positive for myeloid markers varied significantly depending on the mAb clone and the positive threshold. Among patients with B-ALL, the proportion of CD13+ ALL was significantly lower using SJ1D1 than using L138 or My7, while the proportion of CD33+ ALL was significantly higher for My9 than for P67.6 or D3HL60. Analysis of the co-expression of CD13 and CD33 on B-ALL cells using combinations of mAb clones showed that this frequency was either underestimated by the SJ1D1/D3HL60 or overestimated by the L138/P67.6 and My7/My9 combinations. A correlation between CD13/CD33 positivity and the t(12;21) translocation was uniformly observed in B-ALL patients for a positive threshold of 30%, whereas SJ1D1/D3HL60 detected no correlation between t(12;21) and CD13/CD33 positivity when the threshold was lowered to 20%. These data show that the mAb clones commonly used to detect the CD13 and CD33 surface antigens have variable immunoreactivity against childhood ALL cells, which may partly explain the conflicting reports concerning the prognostic significance of myeloid antigen expression in paediatric ALL and its association with different translocations. The present findings may also be of clinical importance for therapeutic choices.

Antibodies, Monoclonal↗
PubMed2006

Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders.

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.

Adult↗
PubMed2003

Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study.

BACKGROUND: The translocation t(12;21)(p13;q22), which produces the TEL/AML1 fusion gene, is the most frequent chromosomal abnormality in patients with childhood acute lymphoblastic leukemia (ALL) and generally is associated with a favorable prognosis. Furthermore, real-time quantitative-polymerase chain reaction (RQ-PCR)-based detection of TEL/AML1 represents an accurate technique for the reproducible assessment of minimal residual disease (MRD). METHODS: The authors employed RQ-reverse transcriptase-PCR (RQ-RT-PCR) technology to analyze MRD levels in 57 newly diagnosed patients with TEL/AML1 positive ALL in a prospective study. RESULTS: On Day + 33, a particularly important time point in terms of outcome prediction based on MRD monitoring, 75% of patients reached negativity, 13% of patients were positive at very low levels (< 10(-4); i.e., 1 or more leukemic cell per 10(4) normal cells), and another 13% of patients were positive at the level of 10(-2) to 10(-4) cells. No patient showed MRD levels > or = 10(-2) cells at this time. The data demonstrate that patients with TEL/AML1 positive ALL had a better response to induction chemotherapy on Day + 33 compared with a group of unselected patients with ALL (P = 0.0001). However, four patients with TEL/AML1 positive ALL developed relapse disease. Remarkably, these children were positive for MRD on Day + 33 at a level between 10(-2) cells and 10(-4) (n = 3 patients) and at < 10(-4) (n = 1 patient). Kaplan-Meier analysis of disease free survival showed the statistical significance of this distribution (MRD positive vs. MRD negative; log-rank P = 0.0016). CONCLUSIONS: The authors conclude that, although the TEL/AML1 positive leukemias generally are associated with a favorable outcome, MRD positivity assessed by RQ-RT-PCR analysis at the end of induction therapy represents a significantly negative prognostic feature.

Adolescent↗
PubMed2003

Post-induction residual disease in translocation t(12;21)-positive childhood ALL.

BACKGROUND: t(12;21)(p1 3;q22), the most frequent chromosomal translocation found in childhood acute lymphoblastic leukemia (ALL), occurs in approximately 25% of B-lineage ALL cases and has been claimed to carry a good prognosis. PROCEDURE: As part of the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-MRD 95 study, which includes children from Iceland, Norway, and Denmark diagnose d with ALL, patients were screened for the presence of t(12; 21) by reverse transcriptase-polymerase chain reaction (RT-PCR) at diagnosis, and their residual disease was quantified after 4 weeks of induction therapy (prednisolone, vincristine, doxorubicin, i.t. methotrexate) by a competitive, clone-specific, semi-nested PCR analysis. RESULTS: Among 96 children diagnosed with ALL, and quantified for post induction residual disease, 32 were t(12;21)-positive. The median residual disease was similar for B-precursor ALL patients with and without t(12;21) (0.009 vs. 0.03%, P = 0.12). CONCLUSIONS: Al though patients with t(12;21)-positive ALL have been claimed to have a good outcome, these data indicate that this does not reflect a high sensitivity to prednisolone, vincristine, and doxorubicin given during induction therapy.

Adolescent↗
PubMed2005

The G-CSF receptor carboxyl terminus, truncated in AML/SCN, is required for induction of a Stat5 protease activity.

Granulocyte colony-stimulating factor (G-CSF) has been shown to stimulate the activation of the signal transducer and activator of transcription 5 (Stat5). We show here that G-CSF-stimulated activation of Stat5 was attenuated when myeloid cells were induced to differentiate with G-CSF. Attenuated activation of Stat5 correlated with reduced Stat5 protein levels, which was associated with upregulation of a Stat5 protease activity. Carboxyl terminal truncation of the G-CSF receptor or expression of leukemogenic proteins Bcr-Abl and Tel-Jak2 abolished the upregulation of the Stat5 protease activity by G-CSF. These data add to our understanding of the roles of G-CSF and Stat5 in normal granulopoiesis and leukemogenesis.

Animals↗
PubMed2003

Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children's Oncology Group study.

Minimal residual disease (MRD) can be detected in the marrows of children undergoing chemotherapy either by flow cytometry or polymerase chain reaction. In this study, we used four-color flow cytometry to detect MRD in 1016 children undergoing therapy on Children's Oncology Group therapeutic protocols for precursor-B-cell ALL. Compliance was excellent, with follow-up samples received at the end of induction on nearly 95% of cases; sensitivity of detection at this time point was at least 1/10,000 in more than 90% of cases. Overall, 28.6% of patients had detectable MRD at the end of induction. Patients with M3 marrows at day 8 were much more likely to be MRD positive (MRD+) than those with M2 or M1 marrows. Different genetically defined groups of patients varied in their prevalence of MRD. Specifically, almost all patients with BCR-ABL had high levels of end-of-induction MRD. Only 8.4% of patients with TEL-AML1 were MRD+>0.01% compared with 20.3% of patients with trisomies of chromosomes 4 and 10. Our results show that MRD correlates with conventional measures of slow early response. However, the high frequency of MRD positivity in favorable trisomy patients suggests that the clinical significance of MRD positivity at the end of induction may not be the same in all patient groups.

Adolescent↗
PubMed2005

Immunogenotype changes prevail in relapses of young children with TEL-AML1-positive acute lymphoblastic leukemia and derive mainly from clonal selection.

PURPOSE: Variations of the immunogenotype and TEL deletions in children with TEL-AML1+ acute lymphoblastic leukemia support the hypothesis that relapses derive from a persistent TEL-AML1+ preleukemic/leukemic clone rather than a resistant leukemia. We aimed at elucidating the relationship between the immunogenotype patterns at diagnosis and relapse as well as their clinical and biological relevance. PATIENTS AND METHODS: Immunoglobulin and T-cell receptor gene rearrangements were analyzed in 41 children with a TEL-AML1+ acute lymphoblastic leukemia and an early (up to 30 months after diagnosis; n = 12) or late (at 30 months or later; n = 29) disease recurrence by a standardized PCR approach. RESULTS: In 68% of the patients (group I), we identified differences in the immunogenotype patterns, whereas no changes were observed in the remaining 32% (group II). The divergence resulted more often from clonal selection than clonal evolution and consisted predominantly of losses (0-6, median 5) and/or gains (0-4, median 1) of rearrangements. The frequency and number of clonal immunoglobulin/T-cell receptor rearrangements in group I was higher at diagnosis (2-13, median 5) than at relapse (2-7, median 4), whereas it was the lowest in group II (1-5, median 3). Although group I children were younger at diagnosis, there was no correlation between particular immunogenotype patterns and remission duration. CONCLUSION: These findings imply that the clonal heterogeneity in younger children most likely reflects an ongoing high recombinatorial activity in the preleukemic/leukemic cells, whereas the more uniform repertoire observed in older children mirrors end-stage rearrangement patterns of selected cell clones that evolved during the prolonged latency period.

Adolescent↗
PubMed1999

Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling.

To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the ets transcription factor TEL and the cytosolic tyrosine kinase Jak2. The effects of these proteins on interleukin-3 (IL-3)-dependent proliferation of the hematopoietic cell line, Ba/F3, were studied. Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in conversion of Ba/F3 cells to factor-independence. Importantly, fusion of TEL to the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no effect on IL-3-dependent proliferation of Ba/F3 cells. Active TEL-Jak2 constructs (consisting of either Jak2 JH1 or Jak2 JH2+JH1 domain fusions) were constitutively tyrosine-phosphorylated but did not affect phosphorylation of endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of phosphorylation using activation-specific antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays. Elucidation of signaling events downstream of TEL-Jak2 activation may provide insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.

Animals↗
PubMed1998

[Usefulness of molecular screening in childhood lymphoblastic leukemias].

PURPOSE: To demonstrate that a molecular screening by reverse transcriptase polymerase chain reaction (RT-PCR) of TEL/AML1, E2A/PBX1 and BCR/ABL genes in pediatric acute lymphoblastic leukaemia is a rapid method that allows one to exceed the percentage of adult patients with the BCR/ABL rearrangement. PATIENTS AND METHODS: 12 Spanish children with acute lymphoblastic leukaemia were studied, 11 of them newly diagnosed and 1 relapsed. The patients were between 18 months and 10 years old. Bone marrow aspiration was collected between april and december 1996, RNA was isolated and cDNA was subjected to PCR amplification for TEL/AML1, E2A/PBX1 and BCR/ABL genes. Normal ABL and E2A genes were studied as amplification controls. RESULTS: One of these hybrid genes was found in 33.3% of patients studied. TEL/AML1 in two cases (16.6%), E2A/PBX1 in one case (8.3%) and BCR/ABL in another one (8.3%). CONCLUSIONS: On the basis of these data it would be useful to achieve a molecular screening of TEL/AML1, E2A/PBX1 and BCR/ABL genes in pediatric acute lymphoblastic leukaemia for allowing a molecular classification in a great percentage of patients that exceed the BCR/ABL positivity in adults.

Aneuploidy↗
PubMed1998

Incidence of TEL/AML1 fusion in children with relapsed acute lymphoblastic leukemia.

The TEL/AML1 fusion associated with t(12;21)(p13;q22) is the most common gene rearrangement in childhood leukemia, occurring in approximately 25% of pediatric acute lymphoblastic leukemia (ALL), and is associated with a favorable prognosis. For example, a cohort of pediatric patients with ALL retrospectively analyzed for the TEL/AML1 fusion treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols between 1980 to 1991 demonstrated a 100% relapse-free survival in TEL/AML1-positive patients with a median of 8.3 years of follow-up. However, two recent studies analyzing pediatric patients with relapsed ALL have reported the same incidence of the TEL/AML1 rearrangement as in patients with newly diagnosed ALL, suggesting that TEL/AML1 positivity is not a favorable prognostic indicator. To clarify this apparent discrepancy, 48 pediatric patients treated on Dana-Farber Cancer Institute (DFCI) protocols with ALL at first or second relapse were tested for TEL/AML1 using reverse transcriptase-polymerase chain reaction (RT-PCR). The TEL/AML1 fusion was identified in only 1 of 32 analyzable relapsed ALL patients, in concordance with our previous reports of improved disease-free survival in TEL/AML1-positive patients. The low frequency of TEL/AML1-positive patients at relapse is significantly different than that reported in other studies. Although there are several potential explanations for the observed differences in TEL/AML1-positive patients at relapse, it is plausible that relapse-free survival in TEL/AML1-positive patients may be changed with different therapeutic approaches. Taken together, these results support the need for prospective analysis of prognosis in TEL/AML1-positive patients.

Adolescent↗
PubMed2004

Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells.

L-Asparaginase is a standard component in chemotherapy of childhood acute lymphoblastic leukaemia (ALL). Leukaemic cells carrying TEL/AML1 fusion gene are more sensitive to treatment with L-asparaginase compared to other subtypes of ALL. We demonstrate in vitro the prolonged growth suppression of TEL/AML1[+] cells compared to TEL/AML1[-] leukaemic cells after L-asparaginase treatment simulating treatment protocol. Cell cycle analysis revealed TEL/AML1[+] cells to accumulate in G1/G0 phase (81-98%) compared to TEL/AML1[-] cells (47-60%). Quantitative analysis of asparagine synthetase (AsnS) expression showed the ability of TEL/AML1[+] cells to increase AsnS mRNA levels after L-asparaginase treatment to the same extent as TEL/AML1[-] leukaemic and nonleukaemic lymphoid cells. We hypothesise that TEL/AML1[+] cells are unable to progress into the S phase of cell cycle under nutrition stress caused by L-asparaginase, despite the ability of AsnS upregulation. Significantly higher expression of AsnS was found in untreated leukaemic cells from children with TEL/AML1[+] ALL (n=20) in comparison with the group of age-matched children with ALL bearing no known fusion gene (n=25; P=0.0043). Interestingly, none of the TEL/AML1[+] patients with high AsnS level relapsed, whereas 10/15 patients with AsnS below median relapsed (P=0.00028). Therefore, high AsnS levels in TEL/AML1[+] patients correlate with better prognosis, possibly reflecting the stretched metabolic demand of the lymphoblast.

Asparaginase↗
PubMed1998

TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin-Frankfurt-Münster Study Group.

The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1-positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph)-positive leukemia. Thus, the incidence of TEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1-positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = . 0001) and age at initial diagnosis (53.5 v 74 months; P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference. TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.

Adolescent↗
PubMed1999

Rapid and sensitive minimal residual disease detection in acute leukemia by quantitative real-time RT-PCR exemplified by t(12;21) TEL-AML1 fusion transcript.

Because previous PCR-based methodologies for detection of minimal residual disease (MRD) in leukemia patients have been too cumbersome to allow for widespread clinical usefulness, we have employed a real-time quantitative PCR (RQ-PCR) system to develop an MRD assay for t(12;21). We initially determined the expression of the different alternatively spliced TEL-AML1 mRNAs found in t(12;21) breakpoint variants I and II. We then optimized PCR primers for the RQ-PCR system and, using the t(12;21)+ REH cell line in spiking experiments, found a linear detection of TEL-AML1 over at least five logs. Moreover, 1 malignant cell in a background of 1,000,000 normal cells could be detected. The expression of the GAPDH, ABL, and beta(2)-microglobulin (beta2M) housekeeping genes were then compared in normal donors and in leukemic patients, and the very stably expressed beta2M was selected as an internal reference gene, allowing us to compensate for variation in RNA quality and day-to-day variation. In 12 samples from t(12;21)-positive patients at diagnosis, the levels of the TEL-AML1 fusion transcripts were found to vary up to 14-fold after normalization to beta2M. Interestingly, in samples obtained from seven patients at diagnosis, during induction chemotherapy, or relapse, the level of TEL-AML1 in peripheral blood (PB) and bone marrow (BM) was found to differ only by threefold, suggesting that MRD may be evaluated in PB samples in most patients. We conclude that this assay could set new standards for t(12;21) MRD detection with its accuracy, its high throughput, and its short turnover time for samples. Genes Chromosomes Cancer 26:355-365, 1999.

Bone Marrow↗
PubMed2002

Spectral karyotyping and interphase FISH reveal abnormalities not detected by conventional G-banding. Implications for treatment stratification of childhood acute lymphoblastic leukaemia: detailed analysis of 70 cases.

Seventy uniformly treated children with acute lymphoblastic leukemia were analysed for chromosomal abnormalities with conventional G-banding, spectral karyotyping (SKY) and interphase fluorescent in situ hybridisation (FISH) using probes to detect MLL, BCR/ABL, TEL/AML1 rearrangements and INK4 locus deletions. Numerical and/or structural changes could be identified in 80% of the patients by the use of molecular cytogenetic techniques, whereas abnormalities could be detected in 60% of the patients using G-banding alone. Altogether, 106 structural aberrations were defined by FISH compared to 34 using G-banding. Seventy-four percent of the patients had numerical aberrations, 54% structural aberrations and 20% had no identified aberrations. Twelve cases had prognostically unfavourable chromosomal aberrations that had not been detected in the G-banded analysis. We identified three novel TEL partner breakpoints on 1q41, 8q24 and 21p12, and a recurrent translocation t(1;12)(p32;p13) was found. In addition, two cases displayed amplification (7-15 copies) of AML1. Our results demonstrate the usefulness of SKY and interphase FISH for the identification of novel chromosome aberrations and cytogenetic abnormalities that provide prognostically important information in childhood ALL.

Adolescent↗
PubMed2006

Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01.

In a retrospective analysis, we previously reported that children whose leukemia cells harbored the TEL/AML1 gene rearrangement have excellent outcomes. From 1996 to 2000, we conducted a prospective study to determine the incidence and outcomes of children with TEL/AML1-positive acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were treated on DFCI ALL Consortium Protocol 95-01. Patients were risk stratified primarily by current National Cancer Institute (NCI)-Rome risk criteria. With a median follow-up of 5.2 years, the 5-year event-free survival for TEL/AML1-positive patients was 89% compared with 80% for TEL/AML1-negative B-precursor patients (P = .05). The 5-year overall survival rate was 97% among TEL/AML-positive patients compared with 89% among TEL/AML1-negative patients (P = .03). However, in a multivariable analysis, risk group (age and leukocyte count at diagnosis) and asparaginase treatment group, but not TEL/AML1 status, were found to be independent predictors of outcome. We conclude that TEL/AML1-positive patients have excellent outcomes, confirming our previous findings. However, factors such as age at diagnosis and presenting leukocyte count should be taken into consideration when treating this group of patients.

Age Factors↗
PubMed2001

Molecular quantification of response to therapy and remission status in TEL-AML1-positive childhood ALL by real-time reverse transcription polymerase chain reaction.

Although TEL-AML1 positivity [translocation t(12;21)(p13;q22)], detected in 20-25% of initial childhood acute lymphoblastic leukemia (ALL), has been associated with an excellent prognosis, its positive predictive value is insufficient for appropriate treatment stratification considering reported prevalence in relapsed ALL (3-28%). Molecular quantification of response to therapy by PCR-based methods has been shown to improve risk assessment. Here, we report on the sensitive quantification of leukemia-specific TEL-AML1 fusion transcript levels normalized to beta-actin expression (sensitivity threshholds, 10(-5)) by a novel real-time reverse transcription-PCR (RQ-RT-PCR) based on fluorescent TaqMan technique providing early and rapid evidence on the treatment efficacy of children with initial or relapsed TEL-AML1+ ALL enrolled in frontline or relapse trials of the Berlin-Frankfurt-Münster (BFM)-Study Group. In initial ALL, TEL-AML1/beta-actin decrease was > or =10(5)-fold in 50% of patients after induction therapy (day 33) and stayed TEL-AML1-negative throughout therapy, which suggested high sensitivity of leukemic cells to antineoplastic therapy. The remaining patients were still TEL-AML1+ before reintensification (ratios, 0.7 x 10(-2):10(-4)). In relapsed ALL, TEL-AML1/beta-actin decrease was generally less pronounced at corresponding time points, and conversion to TEL-AML1 negativity was observed in 40% of patients. Most notably, subsequent relapses occurred only among molecular poor responders, whereas all early responders remain in their second complete remission. In conclusion, real-time quantification of TEL-AML1/beta-actin kinetics distinguishes distinct molecular response groups, and provides indications capable of directing therapeutic interventions for patients with TEL-AML1+ ALL. Before considering modification of therapy, results should be interpreted cautiously taking into account the long duration of remission associated with TEL-AML1+ ALL.

Actins↗