In a recently published review in Blood Advances, the authors focus on the critical role of poly(ADP-ribose) polymerase 1 (PARP1) in the physiological and pathological effects in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), providing a detailed overview of the its mechanisms of action and role in these hematological malignancies. They also highlight the available data and clinical trials on the use of PARP inhibitors (PARPis) in these patient populations.
PARP1 was the first enzyme identified among a family of 18 PARP enzymes that use the oxidized form of nicotinamide adenine dinucleotide (NAD1) to transfer ADP-ribose to other proteins (poly ADP-ribosylation). At least 18 enzymes, all of which share a conserved catalytic domain, are encoded by different PARP genes. PARP1 is involved in a number of cellular processes, including DNA repair, transcriptional and posttranscriptional regulation of gene expression, chromatin remodeling, control of protein degradation, and cell death. It is also overexpressed in a number of cancers, including malignant lymphoma, breast cancer, and colon cancer.
In DNA damage repair, PARP1 is activated by DNA damage, binding to single- and double-strand breaks. When activated, PARP1 uses NAD1 as a substrate to add PAR polymer chains to a number of proteins, including to itself, in a process called PARylation. PARylation leads to the recruitment of several proteins with multiple roles in DNA damage repair. However, lack of function of PARP1 only delays the recruitment of some proteins in DNA damage repair and does not completely impede the process, indicating other pathways are also activated in DNA damage repair.
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Depending on the biological context, PARP1 may support cell survival or death. Repair of low level double-stranded and single-stranded DNA breaks leading to survival of the cell. High levels of DNA damage leads overactivation of PARP1, resulting in cell death due to depletion of NAD and ATP in the cell, and apoptosis, through PARP1 caspase-mediated cleavage. The authors suggest that the next steps in evaluating PARP1 biochemical activities should involve the identification of specific PARP1 PAR targets and understanding of how PAR binding to proteins leads to cytotoxicity.
Some studies have also demonstrated that PARP1 correlated with DNA methylation and silencing of gene expression. This correlation is a key point in the review because hypermethylation is a key event in the pathogenesis of MDS and AML, which is why hypomethylating agents (HMAs) are often effective treatment options for these patients. PARP1 inhibitors have been shown to act synergistically with HMAs by inducing expression of the DNA methyltransferase-1 (DNMT1) gene, leading to reduced methylation.
PARPis, including olaparib, rucaparib, niraparib, veliparib, and talazoparib, are being investigated for use in patients with MDS and AML either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. In addition to PARP1, investigations of novel targets related to other PARP family members are also being conducted and may ultimately be added to the armamentarium of drugs for treating hematological malignancies.
“[Further research] of the mutual expression and regulation of different PARP family members is mandatory to identify possible biomarkers, provide more perspectives for optimal PARPi-based combination outline, and outspread their therapeutic outlook,” concluded the authors.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Kontandreopoulou CN, Diamantopoulos PT, Tiblalexi D, Giannakopoulou N, Viniou NA. PARP1 as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. Blood Adv. 2021;5(22):4794-4805. doi:10.1182/bloodadvances.2021004638
