Prognostic Significance of TEL/AML1 Fusion Transcript in Childhood B-Precursor Acute Lymphoblastic Leukemia

Takahashi, Yoshiyuki; Horibe, Keizo; Kiyoi, Hitoshi; Miyashita, Yoshiko; Fukuda, Minoru; Mori, Hiroshi; Nozaki, Chika; Hasegawa, Shinji; Kawabe, Takashi; Kato, Koji; Kojima, Seiji; Matuyama, Takaharu; Naoe, Tomoki

doi:10.1097/00043426-199805000-00002

Cited by 56 publications

(43 citation statements)

References 16 publications

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“…This was illustrated in the more recent two treatment protocol, showing that the upfront intensive therapy dramatically improved the outcome in the TEL-AML1-positive children (94% vs 66%) at a median follow-up of 57 months (P = 0.25). A similar observation was recently reported from Japan by Takahashi et al 15 A longer follow-up is required before we can definitively conclude that the current protocal is optimal for TEL-AML1-positive children. An alternative may be to apply the augmented chemotherapy during maintenance therapy.…”

Section: Figuresupporting

confidence: 89%

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

Avigad

Kuperstein²,

Zilberstein³

et al. 1999

Leukemia

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CORRESPONDENCE TEL-AML1 fusion transcript designates a favorable outcome with an intensified protocol in childhood acute lymphoblastic leukemia TO THE EDITORDespite the striking success that has been achieved in the treatment of acute lymphoblastic leukemia (ALL), 20-25% of children eventually relapse. 1 Several well-accepted clinical and biological features are of prognostic value: age between 1 and 10 years, leukocyte count of less than 50 000/ l, and hyperdiploid content (DNA index у1.16Ͻ1.60) all predictive of a good outcome. 1 The presence of translocations t(4;11) and t(9;22) confer a poor prognosis and the cryptic translocation t(12;21)(p12;q22), a good prognosis. 2 The t(12;21)(p12;q22) translocation fuses the TEL gene on 12p and the AML1 gene on 21q. 3,4 The predicted hybrid protein includes the region of TEL that is thought to interact with other proteins and to possess transactivating properties together with the DNA binding and transactivating motifs of AML1. In addition, the unrearranged TEL allele is lost in some cases. 5 Several studies have determined that t(12;21) is involved exclusively in B-lineage ALL, mostly in children, and is associated with an excellent prognosis. [6][7][8][9] Recently, however, Borkhardt et al 10 reported that even though patients with the positive chimeric transcript are good responders and achieve CCR, they may develop late relapses. Therefore it is of the utmost importance to identify, at diagnosis, patients in the standard risk group with the tendency to relapse.In the present study, we analyzed 98 B-lineage childhood ALL patients for the TEL-AML1 fusion transcript at diagnosis and correlated the findings with duration of remission according to treatment protocol.Twenty-four of the 98 patients (24%) studied at diagnosis were positive for the TEL-AML1 transcript. The clinical features of the children who were positive or negative for the TEL-AML1 fusion transcript are summarized in Table 1. There were no significant differences between the groups in age, DNA index (DI), leukocyte count, phenotype (CD10 + vs CD10 − ) or response to therapy. Seventy-five percent of the positive patients peaked at age 2-6 although only 38% of the negative patients were in this age group. A recent study showed that the age distribution of TEL-AML1-positive patients peaked at 2-4 years. 11 Eighty-four percent had a leukocyte count of less than 50 000/ l ( Table 1). The majority had a diploid DNA content, generally associated with a less favorable prognosis. Good response to therapy, defined as the achievement of remission by day 23 or before, was noted in 87% of the TEL-AML1-positive children compared to 65% of the TEL-AML1-negative children (P = 0.06).Relapse occurred in 12.5% (3/24) of the positive group and 22% (16/74) of the negative group. The median duration of remission was 56 months and 19 months in the positive and negative groups, respectively.

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Section: Figuresupporting

confidence: 89%

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

Avigad

Kuperstein²,

Zilberstein³

et al. 1999

Leukemia

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“…In Egyptian population, 11.6% frequency of TEL-AML1 transcript was reported in newly diagnosed precursor B-ALL cases of acute lymphoblastic leukemia (Shaker et al, 2001). Frequency of TEL-AML in pediatric ALL patients from Hiroshima Japan was reported to be 10% (Eguchi-Ishimae et al, 1998;Takahashi et al, 1998), while it was reported to be 19% in Nagoya, Japan (Takahashi et al, 1998). Nevertheless, a higher frequency of TEL-AML1 has been reported in pediatric ALL patients in many of the European countries.…”

Section: Discussionmentioning

confidence: 97%

Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

Iqbal

2014

Asian Pacific Journal of Cancer Prevention

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TEL-AML1 fusion oncogene (t 12; 21) is the most common chromosomal abnormality in childhood acute lymphoblastic leukemia (ALL). This translocation is associated with a good prognosis and rarely shows chemotherapeutic resistance to 3-drug based remission induction phase of treatment as well as overall treatment. Thus, the higher the frequency of this fusion oncogene, the easier to manage childhood ALL in a given region with less intensive chemotherapy. Although global frequency of TEL-AML1 has been reported to be 20-30%, a very low frequency has been found in some geographical regions, including one study from Lahore, Punjab, Pakistan and others from India. The objective of present study was to investigate if this low frequency of TEL-AML1 in pediatric ALL is only in Lahore region or similar situation exists at other representative oncology centers of Pakistan. A total of 167 pediatric ALL patients were recruited from major pediatric oncology centers situated in Lahore, Faisalabad, Peshawar and Islamabad. Patients were tested for TEL-AML1 using nested reverse transcription polymerase chain reaction (RT-PCR). Only 17 out of 167 (10.2%) patients were found to be TEL-AML1 positive. TEL-AML1+ALL patients had favorable prognosis, most of them (82.4%, 14/17) showing early remission and good overall survival. Thus, our findings indicate an overall low frequency of TEL-AML1 in Pakistan pediatric ALL patients, in accordance with lower representation of this prognostically important genetic abnormality in other less developed countries, specifically in south Asia, thus associating it with poor living standards in these ethnic groups. It also indicates ethnic and geographical differences in the distribution of this prognostically important genetic abnormality among childhood ALL patients, which may have a significant bearing on ALL management strategies in different parts of the world.

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“…It is possible that a general intensification of therapy, not only by L-Asp but also by other drugs, might contribute to the fact that in some recent protocols, patients with t(12;21)-positive ALL have a favorable outcome. 27 An intensified treatment protocol may also explain the difference in event-free survival of t(12;21)-positive ALL patients between the DCOG and COALL group (5-year eventfree survival of 73 and 80%, respectively). 28,29 The fact that the prognostic value of t(12;21) positive ALL may depend on the therapy that is being given is further illustrated by the fact that Table 1 Prognostic relevance of genetic changes in TEL and/or AML1 and prednisolone resistance in t(12;21)-positive ALL patients Hazard ratio with 95% CI and P-value of patients being intermediate sensitive or resistant to Prednisolone, compared with the reference group of patients being sensitive to prednisolone.…”

Section: Discussionmentioning

confidence: 99%

Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome

et al. 2006

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Clinical heterogeneity within t(12;21) or TEL/AML1-positive ALL (25% of childhood common/preB ALL) indicates that additional genetic changes might contribute to outcome. We studied the relation between additional genetic changes in TEL(ETV6) and AML1(RUNX1) (FISH), drug sensitivity (MTT assay) and clinical outcome in 143 DCOG and COALL-treated t(12;21)-positive ALL patients. Additional genetic changes in TEL and AML1 were present in 83% of the patients, and consisted of (partial) deletion of the second TEL gene (70%), an extra AML1 gene (23%) or an extra der(21)t(12;21) (10%). More than one additional change was observed in 20%. Disease-free survival (pDFS) of DCOG patients without additional genetic changes (4 years pDFS7s.e. 53717%) and of those with an extra der(21)t(12;21) (60722%) is poorer than that of compared to patients with other additional genetic changes in TEL or AML1 (7976%; P-trend ¼ 0.02). This was mainly due to the occurrence of early relapses within 2.5 years after the first diagnosis. Similar observations were found in the COALL cohort, albeit not significant owing to limited follow-up. Multivariate analysis including age, WBC and genetic abnormalities in TEL and/or AML1 showed that especially, in vitro resistance to prednisolone (hazard ratio 5.78, 95% CI 1.45-23.0; P ¼ 0.01) is an independent prognostic factor in DCOG-and COALL-treated t(12;21)-positive ALL.

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Prognostic Significance of TEL/AML1 Fusion Transcript in Childhood B-Precursor Acute Lymphoblastic Leukemia

Cited by 56 publications

References 16 publications

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

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

Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome

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