Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders

Faraoni, Isabella; Giansanti, Manuela; Voso, Maria Teresa; Lo‐Coco, Francesco; Graziani, Grazia

doi:10.1016/j.bcp.2019.04.019

Cited by 20 publications

(21 citation statements)

References 159 publications

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“…As the inhibition of DDR represents a valuable therapeutic option in cancer treatment that could work similarly to ATRA in the treatment of APL [108], targeting TRIM24 or genes belonging to the NER pathway could be considered a possible candidate for APL chemotherapy, as well as patient treatment with alkylating or platinum agents [109]. According to several reports, here we also showed the specific downregulation of PARP-1 and PARP-9 transcripts ( Figure 2B), which are known to be overexpressed in AML cells [110,111] and may represent an intriguing target for AML therapy [112] as well as for APL as suggested by the results reported here. Overall, NER downregulation appears to be a potential strategy to promote myeloid differentiation.…”

Section: Discussionsupporting

confidence: 70%

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Albanesi

Noguera

Banella

et al. 2020

Cells

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Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.

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Section: Discussionsupporting

confidence: 70%

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Albanesi

Noguera

Banella

et al. 2020

Cells

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“…Acute myeloid leukemia (AML) is the most common cause of adult leukemia, contributing to 80% of adult leukemia diagnoses (Yamamoto and Goodman, 2008). Although BRCA1/2 mutations are not characteristic of AML, several pre-clinical studies have demonstrated genomic mutations which provide a rationale for PARPi use in AML therapy (reviewed in Faraoni et al, 2019). It was initially shown that microsatellite instability-positive AML cellular models exhibited down-regulation and mutation of the HR genes CtIP and MRE11 (Gaymes et al, 2013).…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Rose

Burgess

O’Byrne

et al. 2020

Front. Cell Dev. Biol.

401

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The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers. Since then, there has been significant advances in our understanding of the mechanisms behind sensitization of tumors to PARP inhibitors and expansion of the use of PARPi to treat several other cancer types. Here, we review the recent advances in the proposed mechanisms of action of PARPi, biomarkers of the tumor response to PARPi, clinical advances in PARPi therapy, including the potential of combination therapies and mechanisms of tumor resistance.

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“…It is of interest to note that various leukemia-driven oncogenes, such as IDH1/IDH2, TET2, PML-RARA, TCF3-HLF, and RUNX1-RUNXT1 , or treatment with targeted agents directed against aberrant kinases, such as FLT3 and JAK1/2 inhibitors, have been linked to reduced DNA repair activity, a condition that renders leukemic blasts sensitive to PARP inhibitors [ 179 ].…”

Section: Parp Inhibitors Are Effective In Idh1/idh2 Mutant Aml Anmentioning

confidence: 99%

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Testa

Castelli

2020

Cancers

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Acute myeloid leukemia (AML) is a heterogeneous disease generated by the acquisition of multiple genetic and epigenetic aberrations which impair the proliferation and differentiation of hematopoietic progenitors and precursors. In the last years, there has been a dramatic improvement in the understanding of the molecular alterations driving cellular signaling and biochemical changes determining the survival advantage, stimulation of proliferation, and impairment of cellular differentiation of leukemic cells. These molecular alterations influence clinical outcomes and provide potential targets for drug development. Among these alterations, an important role is played by two mutant enzymes of the citric acid cycle, isocitrate dehydrogenase (IDH), IDH1 and IDH2, occurring in about 20% of AMLs, which leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG); this causes a DNA hypermethylation and an inhibition of hematopoietic stem cell differentiation. IDH mutations differentially affect prognosis of AML patients following the location of the mutation and other co-occurring genomic abnormalities. Recently, the development of novel therapies based on the specific targeting of mutant IDH may contribute to new effective treatments of these patients. In this review, we will provide a detailed analysis of the biological, clinical, and therapeutic implications of IDH mutations.

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Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders

Cited by 20 publications

References 159 publications

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

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