Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukaemia treated on the MRC UKALLXII/ECOG E2993 protocol

Department of Pediatrics, Columbia University, New York, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2009; 27(26):4352-6. DOI: 10.1200/JCO.2009.22.0996
Source: PubMed


Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol.
NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome.
NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS; MUT v WT, 51% v 27%, P = .10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72).
NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.

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Available from: Rosemary E Gale, Jan 17, 2014
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    • "High levels of Notch1 and Jagged1 are common in acute myeloid leukemia and chronic lymphocytic leukemia samples from patients, and leukemia cell lines (21). Notch activation is associated with an improved early therapeutic response and increased sensitivity to glucocorticoids (22). Therefore, it is important to investigate the correlation between SLC25 and Notch protein expression in ALL patients. "
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    ABSTRACT: SLC25A38 is a recently identified protein that belongs to the mitochondrial solute carrier family, SLC25. Previous studies have shown that it is a pro-apoptotic protein, which regulates intrinsic caspase-dependent apoptosis. In order to clarify the effect of SLC25A38 protein expression on acute lymphoblastic leukemia (ALL) cells, we detected the expression of SLC25A38 in various cell lines (RPMI 8226, U266, Molt-4 and Jurkat) by western blot analysis. The results indicate that SLC25A38 is highly expressed in the four cell lines. Among 55 leukemia patients (adult, n=32 and infant, n=23), a high expression of SLC25A38 protein was observed in seven infant (7/23, 30.4%) and 15 adult (15/32, 46.9%) ALL patients. Two adult ALL patients that were positive for SLC25A38 were analyzed and the level of SLC25A38 significantly reduced or disappeared following combined chemotherapy, however, reappeared upon ALL recurrence. The expression level was identified to be associated with the proportion of blast cells in the bone marrow. Additionally, SLC25A38 and Notch1 were co-expressed in the four cell lines and the ALL patient samples. The present results show that expression of SLC25A38 is a common feature of ALL cells and may be a novel biomarker for diagnosis, as well as a potential therapeutic target for ALL.
    Oncology letters 05/2014; 7(5):1422-1426. DOI:10.3892/ol.2014.1947 · 1.55 Impact Factor
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    • "A similar result was obtained in the analysis of 141 adult T-ALL patients treated in either the Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) (n = 87) and GRAALL-2003 (n = 54) trials, in which NOTCH1 or FBXW7 mutations correlated with favorable outcome [Asnafi et al. 2009]. However, analysis of a series of T-ALL patients treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/ Eastern Cooperative Oncology Group (ECOG) E2993 protocol found no significant association between NOTCH1 and FBXW7 mutations and prognosis [Mansour et al. 2009]. Similarly, while NOTCH1 and FBXW7 mutations are associated with favorable early response to treatment in pediatric T-ALL, this early advantage did not ultimately translate to long-term outcome in DCOG or COALL protocols and in the EORTC 58881 and 58951 clinical trials [Clappier et al. 2010; Zuurbier et al. 2010]. "
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    ABSTRACT: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights the critical role of NOTCH signaling in the pathogenesis of this disease and has prompted the development of therapeutic approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are strongly synergistic and may overcome the gastrointestinal toxicity associated with systemic inhibition of the NOTCH pathway. In addition, emerging new anti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 antibodies and stapled peptides targeting the NOTCH transcriptional complex in the nucleus.
    06/2013; 4(3):199-210. DOI:10.1177/2040620712471368
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    • "Notch1 has been reported to play a role in T-ALL and ATL, with approximate mutation rates of 50% and 30%, respectively [16,17,21,22]. Notch1 is required for the proliferation and survival of leukemia cells, and its role has been described in recent reviews [23-26]. "
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    ABSTRACT: The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis. Constitutive activation of Notch signaling has been shown to result in excessive cellular proliferation and a wide range of malignancies, including leukemia, glioblastoma and lung and breast cancers. Notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. This minireview focuses on recent advances related to the mechanisms and roles of activated Notch1, Notch2, Notch3 and Notch4 signaling in human lymphocytic leukemia, myeloid leukemia and B cell lymphoma, as well as their significance, and recent advances in Notch-targeted therapies.
    BMC Cancer 11/2011; 11(1):502. DOI:10.1186/1471-2407-11-502 · 3.36 Impact Factor
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