TEL-AML1 fusion transcript designates a favorable outcome with an intensified protocol in childhood acute lymphoblastic leukemia

Abstract 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 (Ph1)-positive leukemia. Thus, the incidence ofTEL-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.

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TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v88.11.4252.4252 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4252-4258 ◽

Cited By ~ 33

Author(s):

TW McLean ◽

S Ringold ◽

D Neuberg ◽

K Stegmaier ◽

R Tantravahi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Chromosomal Translocation ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Polymerase Chain ◽

B Lineage

Abstract Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

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TEL-AML1 Fusion Transcript in Relapsed Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v91.5.1716.1716_1716_1722 ◽

1998 ◽

Vol 91 (5) ◽

pp. 1716-1722 ◽

Cited By ~ 106

Author(s):

Karlheinz Seeger ◽

Hans-Peter Adams ◽

Dirk Buchwald ◽

Birgit Beyermann ◽

Bernhard Kremens ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Philadelphia Chromosome ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia ◽

Long Term Results ◽

Childhood All ◽

Cryptic Translocation

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 (Ph1)-positive leukemia. Thus, the incidence ofTEL-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.

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TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v88.11.4252.bloodjournal88114252 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4252-4258 ◽

Cited By ~ 198

Author(s):

TW McLean ◽

S Ringold ◽

D Neuberg ◽

K Stegmaier ◽

R Tantravahi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Chromosomal Translocation ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Polymerase Chain ◽

B Lineage

Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

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12p Abnormalities and the TEL Gene (ETV6) in Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v90.11.4559 ◽

1997 ◽

Vol 90 (11) ◽

pp. 4559-4566 ◽

Cited By ~ 52

Author(s):

S.C. Raimondi ◽

S.A. Shurtleff ◽

J.R. Downing ◽

J. Rubnitz ◽

S. Mathew ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Genetic Material ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia ◽

Similar Distribution ◽

Event Free Survival ◽

Childhood All ◽

Free Survival ◽

The Status

Abstract Although abnormalities involving the short arm of chromosome 12 (12p) are one of the most frequently observed rearrangements in childhood acute lymphoblastic leukemia (ALL), little is known about the frequency of different structural abnormalities and their relationship to the status of the ETV6 (also named TEL) gene in this region. Of 815 children with newly diagnosed ALL, 94 (11.5%) had a total of 104 cytogenetic 12p abnormalities. Loss of genetic material was observed in 67 (64%) of these abnormalities. Cases with 12p alterations had a much lower frequency of hyperdiploidy greater than 50 (7%) than did the ALL population in general, but these cases had a similar distribution of immunophenotype and similar 5-year event-free survival (70% ± 5% SE v 64% ± 2%, P = .64). Rearrangement of the ETV6 gene was identified in 36 (56%) of 64 cases evaluated. The ETV6-CBFA2 (TEL-AML1) fusion transcript was found in 25 (66%) of 38 cases evaluated, and all but one of these showed ETV6 rearrangement. Importantly, ETV6 rearrangement was associated with a favorable prognosis (5-year event-free survival: 89% ± 6% v 60% ± 1%, P < .01). We conclude that most but not all 12p cytogenetic abnormalities in childhood ALL involve ETV6, and that rearrangement of ETV6 is associated with a favorable treatment outcome.

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Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6–RUNX1 fusion, T-lineage immunophenotype, and favorable outcome

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2006.04.006 ◽

2006 ◽

Vol 169 (1) ◽

pp. 50-57 ◽

Cited By ~ 27

Author(s):

Susana C. Raimondi ◽

Yinmei Zhou ◽

Sheila A. Shurtleff ◽

Jeffrey E. Rubnitz ◽

Ching-Hon Pui ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Favorable Outcome ◽

Childhood Acute Lymphoblastic Leukemia ◽

Blast Cells ◽

B Lineage

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BCR/ABL rearrangement with b3a3 fusion transcript in a case of childhood acute lymphoblastic leukemia

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2008.11.006 ◽

2009 ◽

Vol 189 (2) ◽

pp. 132-137 ◽

Cited By ~ 6

Author(s):

Juwon Kim ◽

Tae Sung Park ◽

Chuhl Joo Lyu ◽

Jaewoo Song ◽

Kyung-A. Lee ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia

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12p Abnormalities and the TEL Gene (ETV6) in Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v90.11.4559.4559_4559_4566 ◽

1997 ◽

Vol 90 (11) ◽

pp. 4559-4566 ◽

Cited By ~ 2

Author(s):

S.C. Raimondi ◽

S.A. Shurtleff ◽

J.R. Downing ◽

J. Rubnitz ◽

S. Mathew ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Genetic Material ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia ◽

Similar Distribution ◽

Event Free Survival ◽

Childhood All ◽

Free Survival ◽

The Status

Although abnormalities involving the short arm of chromosome 12 (12p) are one of the most frequently observed rearrangements in childhood acute lymphoblastic leukemia (ALL), little is known about the frequency of different structural abnormalities and their relationship to the status of the ETV6 (also named TEL) gene in this region. Of 815 children with newly diagnosed ALL, 94 (11.5%) had a total of 104 cytogenetic 12p abnormalities. Loss of genetic material was observed in 67 (64%) of these abnormalities. Cases with 12p alterations had a much lower frequency of hyperdiploidy greater than 50 (7%) than did the ALL population in general, but these cases had a similar distribution of immunophenotype and similar 5-year event-free survival (70% ± 5% SE v 64% ± 2%, P = .64). Rearrangement of the ETV6 gene was identified in 36 (56%) of 64 cases evaluated. The ETV6-CBFA2 (TEL-AML1) fusion transcript was found in 25 (66%) of 38 cases evaluated, and all but one of these showed ETV6 rearrangement. Importantly, ETV6 rearrangement was associated with a favorable prognosis (5-year event-free survival: 89% ± 6% v 60% ± 1%, P < .01). We conclude that most but not all 12p cytogenetic abnormalities in childhood ALL involve ETV6, and that rearrangement of ETV6 is associated with a favorable treatment outcome.

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