Acute myeloid leukemia in children: Current status and future directions

Taga, Takashi; Tomizawa, Daisuke; Takahashi, Hiroyuki; Adachi, Souichi

doi:10.1111/ped.12865

Cited by 75 publications

(91 citation statements)

References 88 publications

(156 reference statements)

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“…Pediatric AML accounts for 15–20% of pediatric leukemia, with survival rates of approximately 70% [66]. In adults, AML is the most common type of leukemia, but only 10–20% of patients older than 60 will be cured [67, 68].…”

Section: Acute Myeloid Leukemia (Aml)mentioning

confidence: 99%

The promise of Janus kinase inhibitors in the treatment of hematological malignancies

Senkevitch

Durum

2017

Cytokine

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The Janus kinases (JAK) are a family of kinases that play an essential role in cytokine signaling and are implicated in the pathogenesis of autoimmune diseases and hematological malignancies. As a result, the JAKs have become attractive therapeutic targets. The discovery of a JAK2 point mutation (JAK2 V617F) as the main cause of polycythemia vera lead to the development and FDA approval of a JAK1/2 inhibitor, ruxolitinib, in 2011. This review focuses on the various JAK and associated components aberrations implicated in myeloproliferative neoplasms, leukemias, and lymphomas. In addition to ruxolitinib, other JAK inhibitors are currently being evaluated in clinical trials for treating hematological malignancies. The use of JAK inhibitors alone or in combination therapy should be considered as a way to deliver targeted therapy to patients.

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Section: Acute Myeloid Leukemia (Aml)mentioning

confidence: 99%

The promise of Janus kinase inhibitors in the treatment of hematological malignancies

Senkevitch

Durum

2017

Cytokine

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“…Despite the recent advances achieved in the treatment of leukemia in children, the prognosis of relapsed and refractory disease remains dismal with more than 50% mortality rate 1–3. Acute and long-term toxicities of current chemotherapy agents often limit their further intensification, thus highlighting an urgent need for novel therapeutic approaches to develop newer, safer treatment protocols.…”

Section: Introductionmentioning

confidence: 99%

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

Meier-Stephenson¹,

Riemer²,

Narendran³

2017

OTT

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PurposeRefractory pediatric leukemia remains one of the leading causes of death in children. Intensification of current chemotherapy regimens to improve the outcome in these children is often limited by the effects of drug resistance and cumulative toxicity. Hence, the search for newer agents and novel therapeutic approaches are urgently needed to formulate the next-generation early-phase clinical trials for these patients.Materials and methodsA comprehensive library of antimicrobials, including eight HIV protease inhibitors (nelfinavir [NFV], saquinavir, indinavir, ritonavir, amprenavir, atazanavir, lopinavir, and darunavir), was tested against a panel of pediatric leukemia cells by in vitro growth inhibition studies. Detailed target modulation studies were carried out by Western blot analyses. In addition, drug synergy experiments with conventional and novel antitumor agents were completed to identify effective treatment regimens for future clinical trials.ResultsSeveral of the HIV protease inhibitors showed cytotoxicity at physiologically relevant concentrations (half-maximal inhibitory concentration values ranging from 1–24 µM). In particular, NFV was found to exhibit the most potent antileukemic properties across all cell lines tested. Mechanistic studies show that NFV leads to the induction of autophagy and apoptosis possibly through the induction of endoplasmic reticulum stress. Furthermore, interference with cell signaling pathways, including Akt and mTOR, was also noted. Finally, drug combination studies have identified agents with potential for synergy with NFV in its antileukemic activity. These include JQ1 (BET inhibitor), AT101 (Bcl-2 family inhibitor), and sunitinib (TK inhibitor).ConclusionHere, we show data demonstrating the potential of a previously unexplored group of drugs to address an unmet therapeutic need in pediatric oncology. The data presented provide preclinical supportive evidence and rationale for future studies of these agents for refractory leukemia in children.

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“…It has previously been reported that AML in children accounts for 25% of pediatric leukemia cases and affects ~180 patients annually in Japan (1). A total of 19,000 cases of AML are diagnosed each year, with ~10,000 of these in the United States (2).…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic analysis of the effects and mechanisms of decitabine and cytarabine on acute myeloid leukemia

Zhou

Liu

Zhang

2017

Molecular Medicine Reports

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Acute myeloid leukemia (AML) is a frequently occurring malignant disease of the blood and may result from a variety of genetic disorders. The present study aimed to identify the underlying mechanisms associated with the therapeutic effects of decitabine and cytarabine on AML, using microarray analysis. The microarray datasets GSE40442 and GSE40870 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially methylated sites were identified in AML cells treated with decitabine compared with those treated with cytarabine via the Linear Models for Microarray Data package, following data pre-processing. Gene Ontology (GO) analysis of DEGs was performed using the Database for Annotation, Visualization and Integrated Analysis Discovery. Genes corresponding to the differentially methylated sites were obtained using the annotation package of the methylation microarray platform. The overlapping genes were identified, which exhibited the opposite variation trend between gene expression and DNA methylation. Important transcription factor (TF)-gene pairs were screened out, and a regulated network subsequently constructed. A total of 190 DEGs and 540 differentially methylated sites were identified in AML cells treated with decitabine compared with those treated with cytarabine. A total of 36 GO terms of DEGs were enriched, including nucleosomes, protein-DNA complexes and the nucleosome assembly. The 540 differentially methylated sites were located on 240 genes, including the acid-repeat containing protein (ACRC) gene that was additionally differentially expressed. In addition, 60 TF pairs and overlapped methylated sites, and 140 TF-pairs and DEGs were screened out. The regulated network included 68 nodes and 140 TF-gene pairs. The present study identified various genes including ACRC and proliferating cell nuclear antigen, in addition to various TFs, including TATA-box binding protein associated factor 1 and CCCTC-binding factor, which may be potential therapeutic targets of AML.

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Acute myeloid leukemia in children: Current status and future directions

Cited by 75 publications

References 88 publications

The promise of Janus kinase inhibitors in the treatment of hematological malignancies

The promise of Janus kinase inhibitors in the treatment of hematological malignancies

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

Bioinformatic analysis of the effects and mechanisms of decitabine and cytarabine on acute myeloid leukemia

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