<i>NOTCH1</i> mutation, <i>TP53</i> alteration and myeloid antigen expression predict outcome heterogeneity in children with first relapse of T-cell acute lymphoblastic leukemia

Hof, Jana; Kox, Corinne; Groeneveld-Krentz, Stefanie; Bandapalli, Obul Reddy; Karawajew, Leonid; Schedel, Katharina; Kunz, Joachim; Eckert, Cornelia; Ludwig, Wolf‐Dieter; Ratei, Richard; Rhein, Peter; Henze, Günter; Muckenthaler, Martina U.; Kulozik, Andreas E.; Stackelberg, Arend von; Kirschner-Schwabe, Renate

doi:10.3324/haematol.2016.157792

Cited by 6 publications

(2 citation statements)

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“…47 In our study, we identify TP53 mutations in 4 of 10 patients with post-allo-SCT relapse, which appears significantly more prevalent than in a previous study reporting TP53 alterations in 30 (11%) of 265 children with first ALL relapse (Fisher's exact test P 5 .02). [48][49][50][51] TP53 mutations are known to confer poor prognosis and are more common in relapsed pediatric ALL compared with initial disease 52 ; however, the substantially increased frequency of TP53 alterations observed in our study for the post-allo-SCT relapses compared with the setting of first pre-allo-SCT relapses reflects selection induced by highly intensive treatment. This fits well with the recent observation that genotoxic stresses promote the clonal expansion of hematopoietic stem cells expressing mutant TP53, increasing the possibility of acquiring additional genetic and/or epigenetic changes.…”

Section: Discussioncontrasting

confidence: 52%

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets

et al. 2019

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Section: Discussioncontrasting

confidence: 52%

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets

et al. 2019

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“…TP53 mutations represent a strong and independent predictor of treatment failure in ALL, with outcomes of patients harboring TP53 mutant disease being particularly dismal [5,6]. Although alterations of TP53 are infrequent at disease presentation (< 15%) in ALL, they are significantly enriched at relapse (up to 30%) and in the high-risk low hypodiploid ALL subgroup (> 90%) [6][7][8][9][10]. Consequently, TP53 mutated ALL remains a particularly challenging and, so far, unaddressed issue in the clinical management of ALL due to the limited therapeutic arsenal available.…”

Section: Introductionmentioning

confidence: 99%

Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia

Bell,

Blair,

Singh

et al. 2023

Cancer Cell Int

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Background Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of TP53-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with TP53 mutations, has not been definitively evaluated. Methods Anti-leukemic effects of adavosertib were investigated using a relapsed TP53 isogenic cell model system, primary patient, and patient-derived ALL samples (n = 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively. Results Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (n = 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of TP53 mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL. Conclusions Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL.

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Biology and Treatment of Relapsed Acute Lymphoblastic Leukemia

Hoogerbrugge,

Hagleitner,

von Stackelberg

2024

Pediatric Oncology

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NOTCH1 mutation, TP53 alteration and myeloid antigen expression predict outcome heterogeneity in children with first relapse of T-cell acute lymphoblastic leukemia

Cited by 6 publications

References 18 publications

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets

Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia

Biology and Treatment of Relapsed Acute Lymphoblastic Leukemia

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