Genetic and epigenetic similarities and differences between childhood and adult AML

Juhl‐Christensen, Caroline; Ommen, Hans Beier; Aggerholm, Anni; Kjeldsen, Eigil; Hasle, Henrik; Hokland, Peter

doi:10.1002/pbc.23397

Cited by 35 publications

(32 citation statements)

References 37 publications

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“…Current multicenter trials investigate the potential therapeutic benefit of molecular MRD monitoring after therapy completion (EudraCT number: 2014‐002195‐90; Clinicaltrials.gov identifier: NCT02450877). In childhood AML, the relative paucity of patients positive for qPCR targets exclusively present in the leukemic blasts lowers the number of patients where disease surveillance can be performed …”

Section: Discussionmentioning

confidence: 99%

Measurable residual disease monitoring using Wilms tumor gene 1 expression in childhood acute myeloid leukemia based on child‐specific reference values

Juul-Dam

Nyvold

Vålerhaugen

et al. 2019

Pediatric Blood & Cancer

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Background Measurable/minimal residual disease (MRD) monitoring can predict imminent hematological relapse in acute myeloid leukemia (AML). The majority of childhood AML patients do not harbor fusion genes or mutations applicable as MRD markers and overexpression of Wilms tumor gene 1 (WT1) may constitute a useful monitoring target. However, age‐specific reference values in healthy hematopoiesis and standardization of WT1 assessment are prerequisites for clinical utility. Procedure We investigated WT1 expression across age in hematologically healthy controls (n = 109), during suspected infection (n = 90) and bone marrow (BM) regeneration (n = 13). WT1 expression in AML at diagnosis (n = 91) and during follow‐up (n = 30) was compared with age‐specific reference values. Results WT1 expression correlated with age and showed higher levels in both BM and peripheral blood (PB) in children compared with adults (P < 0.001 and P = 0.01). WT1 expression from healthy hematopoiesis was lower in PB compared with BM (WT1BM/WT1PB = 8.6, 95% CI: 5.3–13.7) and not influenced by infection nor BM regeneration. At AML diagnosis, 66% had more than 20‐fold WT1 overexpression in PB or BM (PB 74%; BM 45%). WT1 was quantified in 279 PB samples during follow‐up. All 11 patients with PB sampling within 4 months of disease recurrence displayed WT1 overexpression by a median of 1.9 months (range, 0.7–9.7) before hematological relapse. Conclusions This study defines child‐specific reference values for WT1 expression in healthy hematopoiesis and demonstrates that WT1 expression in PB is a useful post‐treatment monitoring tool in childhood AML. Based on these observations, we propose definitions for childhood AML molecular relapse using WT1 overexpression.

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Section: Discussionmentioning

confidence: 99%

Measurable residual disease monitoring using Wilms tumor gene 1 expression in childhood acute myeloid leukemia based on child‐specific reference values

Juul-Dam

Nyvold

Vålerhaugen

et al. 2019

Pediatric Blood & Cancer

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“…Differences in promoter hypermethylation of selected genes between pediatric and adult AML warrant the profiling of DNA methylation in pediatric AML [103]. These studies may point out subsets of patients eligible for treatment with demethylating agents or histone modification inhibitors, as was shown for pediatric ALL [72].…”

Section: Future Strategiesmentioning

confidence: 99%

Pediatric AML: From Biology to Clinical Management

Rooij

2015

JCM

169

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Pediatric acute myeloid leukemia (AML) represents 15%–20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine-containing chemotherapy and stem cell transplantation in selected genetic high-risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%–10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity.

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“…Interestingly, promoter hypermethylation was most frequent in core-binding factor leukemias compared with KMT2A-associated AML. 25 With only 70 patients younger than age 14 studied, further analysis is needed. Nonetheless, it appears that hypermethylation may be a significant leukemogenic event in childhood AML despite mutational patterns that differ from adults.…”

Section: Epigenetic Targeting Mutations Involving Epigenetic Regulatorsmentioning

confidence: 99%

Acute myeloid leukemia in children and adolescents: identification of new molecular targets brings promise of new therapies

Kolb

Meshinchi

2015

Hematology

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Recent reports of recurrent mutations in childhood acute myeloid leukemia (AML) have identified potential targets for new therapeutic strategies. Acute promyelocytic leukemia (APL) is characterized commonly by a fusion between the PML gene and the RARA gene, genes targetable by arsenic (ATO) and retinoic acid (ATRA), respectively. A mutation in GATA1, common in AML of Down syndrome (ML-DS), renders cells more susceptible to cytarabine and anthracyclines, thus permitting targeted dose reductions to preserve high survival rates while reducing toxicity. In all other patients, Ras pathway mutations, KMT2A and other methyltransferase mutations, FLT3 mutations, and KIT mutations are all relatively common in childhood AML and all are potentially "druggable". The focus of this review is on those therapies likely to be clinically available in the near future. The preclinical and clinical data providing a rationale for testing in children of specific agents in children is discussed. Whether the expression of a potential target is sufficient to predict response to a targeted therapy is an open question in childhood AML. Development of clinical trials to evaluate targeted therapies in small molecularly defined subsets of AML will be the next great challenge for all cooperative groups in North America and Europe. Learning Objectives• To understand the potential for targeted therapies and targeted therapeutic approaches for children with AML • To understand the current clinical development status of relevant target therapies in childhood AML • To understand the complexities of clinical trial development for small molecularly defined subsets of childhood AML Acute myeloid leukemia (AML) of childhood accounts for ϳ20% of childhood leukemia diagnoses. Cure rates are approaching 70% (Figure 1), but at the expense of life-altering long-term side effects from high cumulative anthracycline doses for all patients and bone marrow transplant for many patients. Cytogenetic and molecular events now define distinct subsets of childhood AML. With the availability of increasing specific small molecule and antibodybased targeted therapies, clinical trial development is focusing on identifying novel therapies for molecularly defined subsets of disease. The underlying goal of these efforts will be to reduce the toxicity while maintaining or improving survival.

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Genetic and epigenetic similarities and differences between childhood and adult AML

Abstract: Age-related differences exist in the frequency of mutations and it appears that promoter hypermethylation occurs in a non-random pattern in childhood AML accompanying specific genetic aberrations, and might represent an important step in the leukemogenic transformation.

Cited by 35 publications

References 37 publications

Measurable residual disease monitoring using Wilms tumor gene 1 expression in childhood acute myeloid leukemia based on child‐specific reference values

Measurable residual disease monitoring using Wilms tumor gene 1 expression in childhood acute myeloid leukemia based on child‐specific reference values

Pediatric AML: From Biology to Clinical Management

Acute myeloid leukemia in children and adolescents: identification of new molecular targets brings promise of new therapies

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