Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia

Wendy A G Stams; Monique L den Boer; H Berna Beverloo; Jules P P Meijerink; Elisabeth R van Wering; Gritta E Janka-Schaub; Rob Pieters

doi:10.1158/1078-0432.CCR-04-1829

Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia

Wendy A G Stams
, Monique L den Boer
, H Berna Beverloo
, Jules P P Meijerink
, Elisabeth R van Wering
, Gritta E Janka-Schaub
, Rob Pieters

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients.

EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.

RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.

CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.

Original language	English
Pages (from-to)	2974-80
Number of pages	7
Journal	Clin Cancer Res
Volume	11
Issue number	8
DOIs	https://doi.org/10.1158/1078-0432.CCR-04-1829
Publication status	Published - 15 Apr 2005
Externally published	Yes

Keywords

Asparaginase/pharmacology
Cell Survival/drug effects
Child
Chromosomes, Human, Pair 12/genetics
Chromosomes, Human, Pair 21/genetics
Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins/genetics
Disease-Free Survival
Gene Expression Regulation, Neoplastic
Humans
In Situ Hybridization, Fluorescence
Nuclear Proteins/genetics
Oncogene Proteins, Fusion/genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
Prednisolone/pharmacology
Proto-Oncogene Proteins/genetics
Proto-Oncogene Proteins c-ets
RNA, Messenger/genetics
Repressor Proteins/genetics
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors/genetics
Translocation, Genetic
Treatment Outcome
Vincristine/pharmacology

Access to Document

10.1158/1078-0432.CCR-04-1829

Cite this

Stams, W. A. G., den Boer, M. L., Beverloo, H. B., Meijerink, J. P. P., van Wering, E. R., Janka-Schaub, G. E., & Pieters, R. (2005). Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia. Clin Cancer Res, 11(8), 2974-80. https://doi.org/10.1158/1078-0432.CCR-04-1829

@article{bb9d535f2040447fa6bdb5363b6393ae,

title = "Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia",

abstract = "PURPOSE: t(12;21)(p13; q22), present in approximately 25\% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients.EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76\%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95\% confidence interval (95\% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95\% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95\% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.",

keywords = "Asparaginase/pharmacology, Cell Survival/drug effects, Child, Chromosomes, Human, Pair 12/genetics, Chromosomes, Human, Pair 21/genetics, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins/genetics, Disease-Free Survival, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Fluorescence, Nuclear Proteins/genetics, Oncogene Proteins, Fusion/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics, Prednisolone/pharmacology, Proto-Oncogene Proteins/genetics, Proto-Oncogene Proteins c-ets, RNA, Messenger/genetics, Repressor Proteins/genetics, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors/genetics, Translocation, Genetic, Treatment Outcome, Vincristine/pharmacology",

author = "Stams, \{Wendy A G\} and \{den Boer\}, \{Monique L\} and Beverloo, \{H Berna\} and Meijerink, \{Jules P P\} and \{van Wering\}, \{Elisabeth R\} and Janka-Schaub, \{Gritta E\} and Rob Pieters",

year = "2005",

month = apr,

day = "15",

doi = "10.1158/1078-0432.CCR-04-1829",

language = "English",

volume = "11",

pages = "2974--80",

journal = "Clin Cancer Res",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "8",

}

Stams, WAG, den Boer, ML, Beverloo, HB, Meijerink, JPP, van Wering, ER, Janka-Schaub, GE & Pieters, R 2005, 'Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia', Clin Cancer Res, vol. 11, no. 8, pp. 2974-80. https://doi.org/10.1158/1078-0432.CCR-04-1829

Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia. / Stams, Wendy A G; den Boer, Monique L; Beverloo, H Berna et al.
In: Clin Cancer Res, Vol. 11, No. 8, 15.04.2005, p. 2974-80.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia

AU - Stams, Wendy A G

AU - den Boer, Monique L

AU - Beverloo, H Berna

AU - Meijerink, Jules P P

AU - van Wering, Elisabeth R

AU - Janka-Schaub, Gritta E

AU - Pieters, Rob

PY - 2005/4/15

Y1 - 2005/4/15

N2 - PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients.EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.

AB - PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients.EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.

KW - Asparaginase/pharmacology

KW - Cell Survival/drug effects

KW - Child

KW - Chromosomes, Human, Pair 12/genetics

KW - Chromosomes, Human, Pair 21/genetics

KW - Core Binding Factor Alpha 2 Subunit

KW - DNA-Binding Proteins/genetics

KW - Disease-Free Survival

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - In Situ Hybridization, Fluorescence

KW - Nuclear Proteins/genetics

KW - Oncogene Proteins, Fusion/genetics

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics

KW - Prednisolone/pharmacology

KW - Proto-Oncogene Proteins/genetics

KW - Proto-Oncogene Proteins c-ets

KW - RNA, Messenger/genetics

KW - Repressor Proteins/genetics

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Transcription Factors/genetics

KW - Translocation, Genetic

KW - Treatment Outcome

KW - Vincristine/pharmacology

UR - https://www.scopus.com/pages/publications/17144388965

U2 - 10.1158/1078-0432.CCR-04-1829

DO - 10.1158/1078-0432.CCR-04-1829

M3 - Article

C2 - 15837750

SN - 1078-0432

VL - 11

SP - 2974

EP - 2980

JO - Clin Cancer Res

JF - Clin Cancer Res

IS - 8

ER -

Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia

Abstract

Keywords

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