Mutations and Deletions of the <i>TP53</i> Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia

Hof, Jana; Krentz, Stefanie; Schewick, Claudia van; Körner, Gabriele; Shalapour, Shabnam; Rhein, Peter; Karawajew, Leonid; Ludwig, Wolf Dieter; Seeger, Karl; Henze, Günter; Stackelberg, Arend von; Hagemeier, Christian; Eckert, Cornelia; Kirschner-Schwabe, Renate

doi:10.1200/jco.2011.34.8144

Cited by 176 publications

(167 citation statements)

References 35 publications

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“…We retrieved the expected pattern of mutations (supplemental Figure 1; supplemental Table 3) with frequent events in KRAS (13 of 25) and TP53 (10 of 25), consistent with previous reports. 33,34 On average, 74% of single nucleotide variants and insertions/deletions were conserved between the primary diagnostic samples and PDXs ( Figure 1B; supplemental Figure 1). Oncogenic translocations were always maintained.…”

Section: Resultsmentioning

confidence: 99%

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Frismantas

Dobay

Rinaldi

et al. 2017

Blood

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Section: Resultsmentioning

confidence: 99%

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Frismantas

Dobay

Rinaldi

et al. 2017

Blood

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185

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“…35 First, many relapse-acquired lesions involve genes regulating B-cell development (IKZF1), tumor suppression (TP53), 83 Ras signaling, chromatin modification (CREBBP and SETD2), 77 and drug metabolism (NT5C2). 17,35,84 Second, relapseacquired alterations may induce a more stem cell-like state (eg, IKZF1) or directly confer resistance to individual chemotherapeutic agents (eg, CREBBP and NT5C2).…”

Section: Epigenetic Alterations In Allmentioning

confidence: 99%

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

Hunger

Mullighan

2015

Blood

237

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Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches. (Blood. 2015;125(26):3977-3987)

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“…Subsequent genome sequencing has delineated this clonal substructure and evolution and has made several additional observations. 33 Many relapse-acquired lesions are enriched in specific pathways, including B-cell development (IKZF1), tumor suppression (TP53), 34 Ras signaling, chromatin modification (CREBBP, SETD2), 17 and drug metabolism (NT5C2). 33,35 Several of these alterations are known to induce a more stem cell-like state (eg, IKZF1) or confer resistance directly to specific chemotherapy agents such as CREBBP and glucocorticoids 16 and mutations in the 5Ј-nucleotidase gene NT5C2 and nucleoside analogs.…”

Section: Genetic Heterogeneity Clonal Evolution and Relapse In Allmentioning

confidence: 99%

The genomic landscape of acute lymphoblastic leukemia in children and young adults

Mullighan

2014

Hematology

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Our understanding of the genetic basis of childhood acute lymphoblastic leukemia (ALL) has been greatly advanced by genomic profiling and sequencing studies. These efforts have characterized the genetic basis of recently described and poorly understood subtypes of ALL, including early T-cell precursor ALL, Philadelphia chromosome-like (Ph-like) ALL, and ALL with intrachromosomal amplification of chromosome 21, and have identified several rational therapeutic targets in high-risk ALL, notably ABL1-class and JAK-STAT inhibitors in Ph-like ALL. Deep sequencing studies are also refining our understanding of the genetic basis of clonal heterogeneity and relapse. These studies have elucidated the nature of clonal evolution during disease progression and identified genetic changes that confer resistance to specific therapeutic agents, including CREBBP and NT5C2. Genomic profiling has also identified common and rare inherited genetic variants that influence the risk of developing leukemia. These efforts are now being extended to ALL in adolescents and adults with the goal of fully defining the genetic landscape of ALL to further improve treatment outcomes in high-risk populations. Learning Objectives• To understand how molecular approaches, including genome sequencing, have refined the classification of ALL • To appreciate variation in prevalence of ALL subtypes with age • To understand that specific genetic alterations are associated with treatment failure and are potential targets for therapy • To appreciate the relationship between clonal diversity and relapse • To understand the role of inherited genetic variation and risk of developing ALL Childhood acute lymphoblastic leukemiaAcute lymphoblastic leukemia (ALL) is the most common pediatric tumor and, despite event-free survival rates now exceeding 85%, remains the leading cause of cancer-related death in children and young adults due to the often intractable nature of ALL relapse. 1 Although the prevalence of ALL declines with increasing age, the outcome of treatment of ALL in adults is inferior to that of childhood ALL. 2 This is only partly explained by the reduced frequency of genetic alterations associated with favorable outcome in children such as high hyperdiploidy and ETV6-RUNX1 and a rising incidence of adverse genetic alterations such as BCR-ABL1. Furthermore, there are remarkably few therapies targeted to specific genes or pathways and these are urgently needed in view of the dose-limiting toxicities of existing combination chemotherapy.Over the last decade, there have been extensive efforts to use genome-wide profiling of genomic alterations in ALL to: (1) identify additional subtypes of ALL in cases lacking known aneuploidy or chromosomal rearrangements on cytogenetic analysis; (2) characterize the constellations of genetic alterations that define each ALL subtype; (3) identify the nature of clonal heterogeneity and how it influences treatment resistance and relapse; (4) define the role of inherited genetic variants in ALL susceptibility; and (5) transl...

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Mutations and Deletions of the TP53 Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia

Abstract: Alterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.

Cited by 176 publications

References 35 publications

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

The genomic landscape of acute lymphoblastic leukemia in children and young adults

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