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Journal of Clinical Oncology, Vol 19, Issue 13 (July), 2001: 3188-3193
© 2001 American Society for Clinical Oncology

Relapse of TEL-AML1–Positive Acute Lymphoblastic Leukemia in Childhood: A Matched-Pair Analysis

By Karl Seeger, Arend V. Stackelberg, Tillmann Taube, Dirk Buchwald, Gabriele Körner, Meinolf Suttorp, Wolfgang Dörffel, Werner Tausch, Günter Henze

From the Department of Pediatric Oncology/Hematology, Charité Medical Center, Humboldt-University, Berlin; Department of Pediatrics, Christian-Albrechts-Universität, Kiel; Department of Pediatric Oncology, Klinikum Buch, Berlin-Buch; and Department of Pediatric Oncology, Olgahospital, Stuttgart, Germany.

Address reprint requests to Karlheinz Seeger, MD, Department of Pediatric Oncology/Hematology, Otto-Heubner-Centrum, Charité Medical Center, Campus Virchow, Humboldt-University at Berlin, Augustenburger Platz 1, Berlin, Germany, 13353; email: karl.seeger{at}charite.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: The aim of this study was to investigate whether, in relapsed childhood acute lymphoblastic leukemia (ALL), the frequent genetic feature of TEL-AML1 fusion resulting from the cryptic chromosomal translocation t(12;21)(p13;q22) is an independent risk factor.

PATIENTS AND METHODS: A matched-pair analysis was performed within a homogeneous group of children with first relapse of BCR-ABL–negative B-cell precursor (BPC) ALL treated according to relapse trials ALL-Rezidiv (REZ) of the Berlin-Frankfurt-Münster Study Group. A total of 249 patients were eligible for this study: 53 (21%) were positive for TEL-AML1, and 196 (79%) were negative. Positive patients were matched for established most-significant prognostic determinants at relapse, time point, and site of relapse, as well as age and peripheral blast cell count at relapse.

RESULTS: Fifty pairs matching the aforementioned criteria could be determined. The probabilities with SE of event-free survival and survival at 5 years for matched TEL-AML1 positives and negatives are 0.63 ± 0.10 versus 0.38 ± 0.10 (P = .09) and 0.82 ± 0.09 versus 0.42 ± 0.19 (P = .10), respectively. These results were confirmed by multivariate analysis, revealing an independent prognostic significance of time point and site of relapse (both P < .001) but not of TEL-AML1 expression (P = .09).

CONCLUSION: TEL-AML1 expression does not constitute an independent risk factor in relapsed childhood BCP-ALL after matching for relevant prognostic parameters. It undoubtedly characterizes genetically an ALL entity associated with established favorable prognostic parameters. High-risk therapeutic procedures such as allogeneic SCT should be considered restrictively.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
IN INITIAL childhood acute lymphoblastic leukemia (ALL), overall event-free survival (EFS) and survival rates are approaching 80%, with contemporary treatment strategies based on biologic and clinical risk factors.1,2 However, at relapse, despite intensified risk-adapted chemotherapy, overall cure rates of only 35% are achieved.3-5 The established main predictors of outcome at relapse of ALL are time point and site of relapse, as well as the immunophenotype of leukemic cells. Other prognostic parameters relevant for subgroups are age, peripheral blast cell (PBC) count at relapse, and sex, as well as genetic aberrations of leukemic cells.

The prognostic relevance of certain recurrent chromosomal translocations or their molecular equivalents is best illustrated by two frequent genetic aberrations in first relapses of B-cell precursor (BCP) ALL.6,7 The translocation t(9;22)(q34;q11), well known as the Philadelphia chromosome or BCR-ABL, that occurs in 12% of first relapses of BCP-ALL has been shown to be an independent risk factor associated with an adverse prognosis.6,8 In contrast, the prognostic value of TEL-AML1 fusion resulting from the cryptic translocation t(12;21)(p13;q22) is presently not definitively clear. General characteristics of TEL-AML1–positive childhood ALL, both at diagnosis and at relapse, include confinement to B-cell lineage, good response to combination chemotherapy, and a low WBC count, as well as a favorable age distribution.7,9-17 The prevalence of TEL-AML1 fusion in initial childhood ALL is 20% to 25%, and clinical studies have shown an excellent probability of EFS (pEFS 90% to 100%) at 4 years for TEL-AML1–positive patients.9-12 These results probably do not represent final outcomes, considering that TEL-AML1–positive leukemia is biologically characterized by a long duration of first complete remission (CR). Consequently, the majority of relapses (80%) occur off-therapy (median, 3.8 years; range, 1.1 to 10.5 years).7,13,14 Furthermore, different prevalences of TEL-AML1 positivity at relapse of BCP-ALL, ranging from 3% to 28%, have been reported.7,13-17

In all reports of currently applied frontline and relapse ALL trials, TEL-AML1 positivity has been identified as a positive prognostic factor in univariate analyses. To clarify the prognostic significance and clinical relevance of TEL-AML1 fusion in first relapses of BCP-ALL, we performed a matched-pair analysis as well as a multivariate Cox regression analysis in a well-defined group of patients treated according to multicenter relapse trials ALL-Rezidiv (REZ) of the Berlin-Frankfurt-Münster (BFM) Study Group.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
The present study used data from the relapse trials ALL-REZ BFM 87, 90, 95, and 96, conducted by the BFM Study Group. In these multicentric trials, pediatric patients up to 18 years of age with first relapse of ALL from treatment centers in Germany, Austria, and Switzerland diagnosed between 1987 and 2000 were enrolled after written informed consent was obtained from their parents or guardians. The ALL-REZ BFM studies were approved by the institutional review boards of the Freie Universität Berlin and Humboldt-University at Berlin. Inclusion criteria for this study were the availability of all of the following data: duration of first remission, WBC and PBC count at relapse diagnosis, site of relapse, age at initial diagnosis and at relapse, initial treatment, a B-precursor immunophenotype, and no expression of BCR-ABL, as well as data on TEL-AML1 testing analyses at relapse diagnosis. A total of 249 children matched these inclusion criteria. The methods for RNA isolation and molecular detection of TEL-AML1 fusion mRNA have been described previously.7

Therapy
Treatment was based on alternating multiagent courses (R1 and R2).3,4 The frequency of the courses varied from six to 10, depending on the risk group. In trial ALL-REZ BFM 90, a third course, R3, was introduced. For induction therapy, defined subgroups of the trials ALL-REZ BFM 87, 95, and 96 received a F1 and F2 course.4 Most of the patients with available matched-sibling stem-cell donors had undergone transplantation in second CR. Allogeneic bone marrow transplantation from unrelated donors has generally been performed in high-risk patients only (S3 and S4, see Definitions). Cranial irradiation at an age-dependent dose was applied to all children with CNS and/or bone marrow involvement at relapse. Maintenance therapy consisted of biweekly methotrexate, oral etoposide pulses, and daily oral 6-thioguanin, with a total duration of 40 to 70 weeks, depending on the risk group.3,4

Matching Procedure
To match TEL-AML1–positive and –negative patients, the following strategy was applied: no mismatch was permitted for the time point of relapse, site, PBC count, and age at relapse (see definitions). Duration of first remission as continuous parameter with the highest prognostic significance was matched as closely as possible, acting as the main selection criteria for the individual match partner.

Definitions
Time point of relapse was defined as follows: very early, before 18 months after first diagnosis of ALL; early, 18 months after first diagnosis of ALL until 6 months after cessation of frontline therapy; or late, more than 6 months after cessation of frontline therapy. Site of relapse was defined as isolated bone marrow (BM), combined BM, or isolated extramedullary (CNS, testis, or other extramedullary sites). The PBC count was divided into three categories, less than 1/µL, 1 to 10,000/µL, and >= 10,000/µL.18 Age at relapse was divided into three categories: < 5, 5 to 10, and >= 10 years. The ALL immunophenotype was defined as pro-B ALL (CD19+, CD10-, cyIgM-); common ALL (CD19+, CD10+, cyIgM-); pre-B ALL (CD19+, CD10+, cyIgM+). Strategy groups S1 to S4, according to trial ALL-REZ BFM 95 and 96, were defined as follows: S1, late isolated extramedullary relapse; S2, late isolated and late or early combined BM relapse of a BCP ALL, as well as early and very early isolated extramedullary relapse; S3, early isolated BM relapse of a BCP-ALL; S4, very early BM relapse of a BCP ALL or any BM involving relapse of a T-cell ALL.4 Median follow-up was defined as median EFS of patients in complete continuous remission. Median observation time was defined as median interval between date of analysis and date of diagnosis.

Statistical Analysis
Statistical analysis entailed Pearson (product-moment) correlation, Mann-Whitney U-test, Fisher’s exact test, and survival analyses using the Kaplan-Meier method and multivariate Cox regression with proportional hazards. The level of significance was set to a P value <= .05. Computations were performed using SPSS for Windows software, version 9.0 (SPSS Inc, Chicago, IL). EFS was computed from the date of remission to the date of analysis or the date of an adverse event. In cases of nonresponse to therapy or death during induction, EFS was set to 0. EFS was censored at the date of bone marrow transplantation for survival analysis only showing the results of chemotherapy.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 53 of 249 children with first relapse of BCR-ABL–negative BCP-ALL (18.7%) were found to be positive for TEL-AML1 fusion. The 53 positive patients were matched according to the aforementioned rules to the 196 TEL-AML1–negative patients. Fifty pairs meeting the match criteria could be determined. Three TEL-AML1–positive patients remained without a matched partner (ie, excluded positive patients) as well as 146 TEL-AML1–negative (ie, excluded negative) patients.

Patient Characteristics
Patient characteristics according to TEL-AML1 expression and the match status are given in Tables 1 and 2. For the matched pairs, all exactly matched parameters were equally distributed. However, there was a significant difference in the distribution of BCP immunophenotypes. This criteria was not included in the matching procedure because it lacks any prognostic relevance in patients with relapsed ALL. A significant difference was found for age at relapse, time point of relapse, and distribution of S groups between matched TEL-AML1–positive as well as –negative patients and excluded TEL-AML1–negative patients. Distribution of the continuous parameters of duration of first CR, logarithm of PBC at relapse, and age at first diagnosis, relapse, follow-up, and observation time was not significantly different between the matched pair groups. Furthermore, Pearson correlation coefficients revealed a high correlation in both groups for duration of first CR (0.94) and PBC (0.83) as well as for age at relapse (0.73) and at initial diagnosis (0.79). Comparing the matched pairs with the excluded negative patient group, duration of first CR was the only continuous criteria that revealed a significant difference.


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  		Table 1. Characteristics of Patients With First Relapse of ALL
 
Most patients had received frontline therapy according to ALL-BFM or Cooperative ALL protocols. Front-line therapy was comparable in the matched patient groups as well as the excluded negative group. Treatment at relapse, according to the trials ALL-REZ BFM 87, 90, 95, and 96, was equally distributed between the matched groups. Stem-cell transplantation was performed in the minority of patients, and rate of patients who underwent transplantation was comparable in both matched groups (Table 1)Go.


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  		Table 2. Characteristics of Patients With First Relapse of ALL
 
Events and Survival
The matched groups did not differ in respect to response to therapy. A second remission could be induced in 98% of the TEL-AML1–positive and in 96% of the –negative patients. In contrast, the remission rate of the excluded TEL-AML1 negative patients of 83% was significantly worse compared with the matched positive (P = .013) and negative (P = .037) patients because of 12% of the patients did not respond to induction therapy and 5% suffered an induction death (Table 3). At a median observation time of 2.77 years (range, 0.28 to 12.81 years), the pEFS at 5 years is 0.63 (SD = 0.10) for matched TEL-AML1–positive patients and 0.38 (SD = 0.10) for –negative patients. Although there is a trend toward a better pEFS and overall survival for the matched TEL-AML1–positive group, this difference was not significant (P = .09 and .10 respectively) (Fig 1). In contrast, pEFS (0.28 ± 0.07) and overall survival (0.38 ± 0.07) of the excluded negative group is significantly worse compared with the matched positive (P < .001 and P < .001, respectively) as well as the matched negative group (P = .028 and P = .007, respectively). Multivariate Cox regression analysis using the forward Wald method for stepwise entry of covariates into the model revealed time point (P < .001; risk ratio for adverse event: early/late = 6.0; very early/late = 13.4) and site of relapse (P < .001; risk ratio for adverse event: combined/isolated-extramedullary = 1.4; isolated-BM/isolated-extramedullary = 4.7) as the only significant independent predictors for disease-free survival. Expression of TEL-AML1 (P = .09), sex (P = .47), age at first diagnosis (P = .21) and at relapse (P = .44), BCP immunophenotype (P = .06), and PBC count (P = .13) did not show an independent prognostic relevance.


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  		Table 3. Events by TEL-AML1 Expression and Match Status
 


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  		Fig 1. Kaplan-Meier estimates of pEFS (left) and survival (right) for matched pairs by presence of TEL-AML1 fusion and excluded TEL-AML1–negative patients. Results of chemotherapy only (bone marrow transplant censored). Tick marks represent censored observations. —, matched positive (n = 50; EFS: censored = 39; pEFS = .63 ± .10; survival: censored = 44); ---, matched negative (n = 50; EFS: censored = 32; pEFS = .38 ± .10; survival: censored = 40); ----, excluded negative (n = 146; EFS: censored = 80; pEFS = .27 ± .07; survival: censored = 93, pSRV = .37 ± .07).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The molecular characterization of the cryptic recurrent chromosomal translocation t(12;21) in childhood ALL and the identification of the involved genes, TEL and AML1, in 199510,19 initiated a number of studies on the molecular role of the resulting TEL-AML1 fusion oncoprotein and on the clinical significance of TEL-AML1 positivity in childhood ALL. TEL and AML1, both transcription factors, are essential for definitive hematopoiesis.20-22 AML1 is a component of the heterodimeric core binding factor complex presumably involved in the regulation of G1 to S transition.23 Both gene loci are independently involved in several translocations in acute and chronic leukemias as well as myelodysplastic syndromes.24-26 Mutations of AML1 and translocation-derived AML1 fusion oncoproteins have been shown to inhibit core binding factor transactivation in cell lines,21,23,27,28 and, thereby, to induce cell cycle inhibition and prevent cell proliferation.27,29 The chimeric TEL-AML1 protein interferes with AML1-dependent gene regulation in a dominant negative manner.21,30,31 The relevance of TEL-AML1–induced transcriptional inhibition is supported by the finding that TEL-AML1–positive cells demonstrate a prolonged doubling time in vitro, generally low leukocyte counts in vivo, and a long duration of first CR.7,9-12,15,32

Both in newly diagnosed and relapsed childhood ALL, TEL-AML1 fusion represents the most frequent genetic rearrangement in childhood ALL in the BFM studies, and TEL-AML1 positivity has been associated with a favorable outcome at both stages of disease. These apparently conflicting data, as well as the published enormous variation in the frequency of TEL-AML1 positivity in relapsed childhood BCP-ALL (3% to 28%), suggest that the prognostic impact of TEL-AML1 fusion could be partially dependent on the design of frontline therapy. Both Ayigad et al33 and Takahashi et al34 report on an improved outcome of TEL-AML1-positive patients by treatment intensification in Israeli BFM-like and in Japanese frontline studies, respectively. Moreover, in vitro data suggest that patients with TEL-AML1–positive ALL might benefit from therapeutic regimens containing higher cumulative L-asparaginase doses.35 Whether the potentially beneficial effect of higher L-asparaginase dose-intensity in various frontline protocols is linked to the different incidences reported at relapse warrants prospective long-term follow-up data on the prevalence of TEL-AML1 from international trials. The majority of the retrospective analyses on TEL-AML1 prevalence at relapse included only a limited number of patients (32 patients, Dana-Farber Cancer Institute16; 49 patients, St Jude17) and do not permit a definite conclusion.

It has been shown that TEL-AML1 is tied to known risk factors at relapse, such as duration of remission, immunophenotype, and age at initial diagnosis.7,13-17 To assess whether TEL-AML1 also represents an independent risk factor at relapse, a matched-pair analysis was performed that adjusted for the major risk factors, namely: time point and site of relapse, immunophenotype, duration of first remission, PBC count, and age. The distribution of categorical and continuous parameters between the matched TEL-AML1–positive group and the excluded TEL-AML1–negative group confirms the association of TEL-AML1 expression to favorable established risk factors, namely a longer duration of first CR and an intermediate age. This difference could be completely eliminated for the matched negative group, which in fact revealed the same significant difference to the excluded negative group.

This selection effect, above all, had a significant effect on the rate of remission induction, which was comparable between the matched patient groups but significantly better than in the excluded negative group. Whereas the relapse and complete continuous remission rate was not significantly different between the matched groups, a significant difference was found between the matched positive and the excluded negative patients. EFS and survival rates were significantly worse for excluded negative as compared with matched positive or negative patients, indicating that association to a longer duration of first CR has a significant impact on EFS. However, EFS and survival rates 5 years after ALL relapse diagnosis of the matched groups were not significantly different, although a trend toward a better outcome of the matched TEL-AML1–positive group (pEFS = 0.63; probability of survival = 0.82) as compared with the matched negative group (pEFS = 0.38; probability of survival = 0.42) could be shown. These results are supported by the multivariate analysis, again revealing a trend but not an independent prognostic significance of TEL-AML1 expression for disease-free survival. Because follow-up and observation time of the patients were comparably short, and an association of TEL-AML1 expression to a longer second CR has been reported, late events might influence the results of the analysis.

In a previous study, the remission rate (66% v 90%; P < .001) and EFS (0.46 v 0.11; P < .001) of matched BCR-ABL–positive and –negative patients differed significantly, and BCR-ABL could be determined as an independent prognostic factor in addition to established parameters.8 This study demonstrates that the genetic marker TEL-AML1 does not seem to have an independent prognostic significance, if the association to several favorable prognostic factors is considered. It characterizes a group of patients with a favorable prognosis achieved with conventional chemotherapy. In general, a remission can be induced in all TEL-AML1–positive patients and at least a tendency toward fewer subsequent relapses in the matched positive group could be shown. The pEFS above 50% of the TEL-AML1–positive group after chemotherapy alone should be considered as a decision criterion for postremission strategy, in particular concerning allogeneic stem-cell transplantation from unrelated donors.

One last issue to be considered relates to the usefulness of TEL-AML1 fusion transcripts as leukemia-specific markers for sensitive molecular assessments of responses to therapy and as additional criteria for relapse risk and treatment stratification in approximately 20% of childhood ALL cases. It is evident that TEL-AML1–positive leukemia is a heterogenous disease, and it has been shown that sensitive quantification of leukemic cell clearance during initial phases of therapy permits a better risk assessment.36,37 The application of a standardized real-time polymerase chain reaction technique based on the amplification of TEL-AML1 fusion cDNA might contribute to the improvement of relapse risk assessment and the evaluation of therapeutic procedures and to facilitating treatment decisions, which will enable molecular remissions to be achieved and improve clinical outcome in this group of patients.


   ACKNOWLEDGMENTS
 
The study was supported by Deutsche José Carreras Leukämiestiftung, München, and Deutsche Kinderkrebsstiftung, Bonn, Germany.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Kersey JH: Fifty years of studies of the biology and therapy of childhood leukemia. Blood 92: 1838-1849, 1998[Free Full Text]

2. Pui CH: Recent advances in the biology and treatment of childhood acute lymphoblastic leukemia. Curr Opin Hematol 5: 292-301, 1998[Medline]

3. Henze G, Fengler R, Hartmann R: Chemotherapy for relapsed childhood acute lymphoblastic leukemia: Results of the BFM Study Group. Haematol Blood Transfus 36: 374-379, 1994

4. Henze G: ALL-REZ BFM 96: Therapiestudie zur Behandlung von Kindern mit Rezidiv einer ackuten lymphoblastischen Leukämie (ALL), Berlin, Germany, 1996

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6. Beyermann B, Agthe AG, Adams HP, et al: Clinical features and outcome of children with first marrow relapse of acute lymphoblastic leukemia expressing BCR-ABL fusion transcripts: BFM Relapse Study Group. Blood 87: 1532-1538, 1996[Abstract/Free Full Text]

7. Seeger K, Adams HP, Buchwald D, et al: TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia: The Berlin-Frankfurt-Munster Study Group. Blood 91: 1716-1722, 1998[Abstract/Free Full Text]

8. Beyermann B, Adams HP, Henze G: Philadelphia chromosome in relapsed childhood acute lymphoblastic leukemia: A matched-pair analysis—Berlin-Frankfurt-Munster Study Group. J Clin Oncol 15: 2231-2237, 1997[Abstract/Free Full Text]

9. Rubnitz JE, Downing JR, Pui CH, et al: TEL gene rearrangement in acute lymphoblastic leukemia: A new genetic marker with prognostic significance. J Clin Oncol 15: 1150-1157, 1997[Abstract/Free Full Text]

10. Shurtleff SA, Buijs A, Behm FG, et al: TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9: 1985-1989, 1995[Medline]

11. McLean TW, Ringold S, Neuberg D, et al: TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 88: 4252-4258, 1996[Abstract/Free Full Text]

12. Borkhardt A, Cazzaniga G, Viehmann S, et al: Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials: Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster Study Group. Blood 90: 571-577, 1997[Abstract/Free Full Text]

13. Seeger K, Buchwald D, Taube T, et al: TEL-AML1 positivity in relapsed B cell precursor acute lymphoblastic leukemia in childhood: Berlin-Frankfurt-Munster Study Group. Leukemia 13: 1469-1470, 1999[Medline]

14. Seeger K, Buchwald D, Peter A, et al: TEL-AML1 fusion in relapsed childhood acute lymphoblastic leukemia. Blood 94: 374-376, 1999[Free Full Text]

15. Harbott J, Viehmann S, Borkhardt A, et al: Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood 90: 4933-4937, 1997[Abstract/Free Full Text]

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18. Buhrer C, Hartmann R, Fengler R, et al: Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome: Berlin-Frankfurt-Munster Relapse Study Group. J Clin Oncol 14: 2812-2817, 1996[Abstract/Free Full Text]

19. Golub TR, Barker GF, Bohlander SK, et al: Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA 92: 4917-4921, 1995[Abstract/Free Full Text]

20. Wang LC, Swat W, Fujiwara Y, et al: The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes Dev 12: 2392-2402, 1998[Abstract/Free Full Text]

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26. Rubnitz JE, Pui CH, Downing JR: The role of TEL fusion genes in pediatric leukemias. Leukemia 13: 6-13, 1999[Medline]

27. Cao W, Adya NB-B, M., Liu PP, et al: The core binding factor (CBF) alpha interaction domain and the smooth muscle myosin heavy chain (SMMHC) segment of CBFbeta-SMMHC are both required to slow cell proliferation. J Biol Chem 273: 31534-3140, 1998[Abstract/Free Full Text]

28. Zent CS, Mathieu C, Claxton DF, et al: The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties. Proc Natl Acad Sci USA 93: 1044-1048, 1996[Abstract/Free Full Text]

29. Song WJ, Sullivan MG, Legare RD, et al: Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23: 166-175, 1999[Medline]

30. Uchida H, Downing JR, Miyazaki Y, et al: Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter. Oncogene 18: 1015-1022, 1999[Medline]

31. Kwiatkowski BA, Bastian LS, Bauer TR, et al: The ets family member Tel binds to the Fli-1 oncoprotein and inhibits its transcriptional activity. J Biol Chem 273: 17525-17530, 1998[Abstract/Free Full Text]

32. Uphoff CC, MacLeod RA, Denkmann SA, et al: Occurrence of TEL-AML1 fusion resulting from (12;21) translocation in human early B-lineage leukemia cell lines. Leukemia 11: 441-447, 1997[Medline]

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36. Cave H, van der Werff ten Bosch J, Suciu S, et al: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia: European Organization for Research and Treatment of Cancer–Childhood Leukemia Cooperative Group. N Engl J Med 339: 591-598, 1998[Abstract/Free Full Text]

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Submitted January 8, 2001; accepted April 3, 2001.


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E. R. Panzer-Grumayer, G. Cazzaniga, V. H.J. van der Velden, L. del Giudice, M. Peham, G. Mann, C. Eckert, A. Schrauder, G. Germano, J. Harbott, et al.
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