Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial

Jenkinson, Sarah; Kirkwood, Amy A.; Goulden, Nicholas; Vora, Ajay; Linch, David C.; Gale, Rosemary E.

doi:10.1038/leu.2015.206

Cited by 62 publications

(60 citation statements)

References 38 publications

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“…36 This was not confirmed in the MRC UKALL2003 trial for pediatric T-ALL; RAS and/or PTEN aberrations also did not change the favorable outcome of patients with NOTCH1/FBWX7 mutations. 44 Taken together, these findings suggest that PTEN aberrations may represent a general, poor prognostic factor in T-ALL.…”

Section: Discussionmentioning

confidence: 79%

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

et al. 2016

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T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of developing T cells in the thymus. T-ALL is characterized by chromosomal rearrangements. These rearrangements can lead to the aberrant activation of oncogenic transcription factors by placing their genes under the control of promoters and/or enhancers of Tcell receptor genes, the BCL11B gene, or other genes; occasionally, these rearrangements can give rise to oncogenic fusion proteins. The activated oncogenic transcription factors include TAL1 and LMO2 (and related family members), TLX1, TLX3, NKX2-1, HOXA, and MEF2C; in addition, certain oncogenic fusion proteins can directly activate the HOXA or MEF2C genes.1,2 Oncogenic proteins facilitate the developmental arrest of pre-leukemic immature T cells. We previously proposed that these chromosomal rearrangements should be classified as type A aberrations, as they are generally considered to be the driving oncogenic event associated with unique expression profiles.2 Based upon their gene expression signatures, T-ALL can be classified into the following four major subtypes: ETP-ALL, TLX, proliferative, and TALLMO. [3][4][5] Maturation arrest induces a pre-leukemic condition in which additional mutations can give rise to T-ALL.1,2 These secondary mutations are not necessarily clonal events and are often selected during disease progression or post-treatment T he tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycoly sis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.

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Section: Discussionmentioning

confidence: 79%

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

et al. 2016

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“…Neither PTEN nor K/N-RAS genotype significantly impacted outcome, and there was no evidence that they changed the highly favorable outcome of patients with double N/F mutations. 44 Application of the N/F/R/P classifier presented here to this cohort did, however, show a trend towards an inferior OS outcome, but not an inferior relapse-free survival outcome. The reasons for this discordance merit closer examination but potentially include minor treatment variables, the relatively small size of the UKALL cohort, and/or different molecular techniques and/or interpretation, because the incidence of PTEN abnormalities was slightly higher in the UKALL2003 cohort (22%) than the FRALLE2000 cohort (14%).…”

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confidence: 93%

“…The incidence of N/F (61%), PTEN (14%) and K/N RAS (8%) aberrations were similar to other pediatric T-ALL series. 22,24,40,41,43,44 Recently, 145 pediatric T-ALLs treated on the UKALL2003 trial were tested for PTEN/K/N-RAS and N/F mutations. Neither PTEN nor K/N-RAS genotype significantly impacted outcome, and there was no evidence that they changed the highly favorable outcome of patients with double N/F mutations.…”

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confidence: 99%

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia

Petit

Trinquand

Chevret

et al. 2018

Blood

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K E Y P O I N T Sl In pediatric T-ALL, oncogenetic markers, MRD, and WBC count are independent predictors of outcome.l These factors should be used together for individual treatment stratification.Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/ FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n 5 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n 5 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10 24, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ‡200 3 10 9 /L, gHiR classifier, and MRD ‡10 24 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 3 10 9 /L, gLoR classifier, and MRD <10 24 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ‡200 3 10 9

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“…45 As already noted for JAK/STAT, RAS/PTEN alterations are a common feature of T-ALL; their prognostic impact is still controversial in childood. [46][47][48][49] In particular, in their study of children treated with the Berlin-FrankfurtMunster protocol, Bandapalli et al reported that patients with PTEN and NOTCH1 mutations had a marked sensitivity to induction treatment and excellent long-term outcome, similar to that of patients with NOTCH1 mutations only and more favorable than that of patients with PTEN mutations only. 48 The study of Jenkinson et al on pediatric patients treated on the Medical Research Council UKALL2003 trial showed that neither PTEN nor RAS genotypes have a significant impact on response to therapy or long-term outcome; it was also shown that neither PTEN nor RAS genotypes affect the highly favorable outcome of patients with concomitant NOTCH1/FBXW7 mutations.…”

Section: A B Cmentioning

confidence: 99%

“…48 The study of Jenkinson et al on pediatric patients treated on the Medical Research Council UKALL2003 trial showed that neither PTEN nor RAS genotypes have a significant impact on response to therapy or long-term outcome; it was also shown that neither PTEN nor RAS genotypes affect the highly favorable outcome of patients with concomitant NOTCH1/FBXW7 mutations. 49 Conversely, the GRAALL group reported that the favorable prognostic significance of NOTCH1/FBXW7 mutations was restricted to adult patients without RAS/PTEN abnormalities. In fact, K/N-RAS mutations and/or PTEN gene alterations have been associated with poor prognosis.…”

Section: A B Cmentioning

confidence: 99%

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

et al. 2016

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Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.

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Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial

Cited by 62 publications

References 38 publications

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

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