<i>TP53</i>Mutations in Hypodiploid Acute Lymphoblastic Leukemia

Comeaux, Evan Q.; Mullighan, Charles G.

doi:10.1101/cshperspect.a026286

Cited by 57 publications

(50 citation statements)

References 73 publications

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“…LH ALL was characterized by alteration of TP53 in virtually all cases (>91% of LH B-ALL patients; refs. 3,8,9), with up to 40% of these mutations observed in nontumor cells (3), and recurrent somatic deletions in IKZF2 (53%). NH tumors were characterized by Ras/MAPK pathway activation via NRAS mutations (15%) or homozygous deletions in NF1 (44%) or IKZF3 (13%).…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

et al. 2019

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Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patientderived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199-induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL.Significance: These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.

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Section: Introductionmentioning

confidence: 99%

Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

et al. 2019

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“…6,8,9 The most common malignancies that occur in LFS include breast cancer, sarcomas, and brain tumors, whereas leukemias are relatively uncommon 10 ; however, recent reports have also implicated germline TP53 variation in the pathogenesis of hypodiploid acute lymphoblastic leukemia (ALL) in children. [11][12][13] ALL is the most common cancer in children, and there is growing evidence for inherited susceptibility to this malignancy. 14,15 For example, common germline genetic polymorphisms that affect genes that are involved in lymphoid development and tumor suppression-for example, ARID5B, 16,17 IKZF1, 16,17 CEBPE, 17 GATA3, 18,19 CDKN2A, 20,21 BMI-PIP4K2A, 22 and TP63 23 -have been associated with the risk of developing ALL in an age-and subtype-specific fashion.…”

Section: Introductionmentioning

confidence: 99%

TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children

Qian

Cao

Devidas

et al. 2018

JCO

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129

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Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li-Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children's Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P < .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P < .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P < .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P < .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% ( P < .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.

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“…This higher-than-expected rate has prompted the recommendation that all patients with hypodiploid ALL undergo genetic counseling and testing for germline TP53 mutations to facilitate appropriate cancer screening for patients and their family members. 40…”

Section: Li-fraumeni Syndrome and Hypodiploid Allmentioning

confidence: 99%

Pediatric leukemia susceptibility disorders: manifestations and management

McReynolds

Savage

2017

Hematology

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The clinical manifestations of inherited susceptibility to leukemia encompass a wide phenotypic range, including patients with certain congenital anomalies or early-onset myelodysplastic syndrome (MDS) and some with no obvious medical problems until they develop leukemia. Leukemia susceptibility syndromes occur as a result of autosomal dominant, autosomal recessive, or X-linked recessive inheritance, or de novo occurrence, of germline pathogenic variants in DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, and other critical cellular processes. Children and adults with cytopenias, MDS, dysmorphic features, notable infectious histories, immunodeficiency, certain dermatologic findings, lymphedema, unusual sensitivity to radiation or chemotherapy, or acute leukemia with a family history of early-onset cancer, pulmonary fibrosis, or alveolar proteinosis should be thoroughly evaluated for a leukemia susceptibility syndrome. Genetic testing and other diagnostic modalities have improved our ability to identify these patients and to counsel them and their family members for subsequent disease risk, cancer surveillance, and therapeutic interventions. Herein, the leukemia susceptibility syndromes are divided into 3 groups: (1) those associated with an underlying inherited bone marrow failure syndrome, (2) disorders in which MDS precedes leukemia development, and (3) those with a risk primarily of leukemia. Although children are the focus of this review, it is important for clinicians to recognize that inherited susceptibility to cancer can present at any age, even in older adults; genetic counseling is essential and prompt referral to experts in each syndrome is strongly recommended.

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TP53Mutations in Hypodiploid Acute Lymphoblastic Leukemia

Cited by 57 publications

References 73 publications

Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children

Pediatric leukemia susceptibility disorders: manifestations and management

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