Targeted therapies selectively block essential biochemical pathways or mutant proteins required for tumor cell growth and survival.
Study: Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells. Image Credit: Immersion Imagery/Shutterstock.com
Despite the improved clinical outcomes for patients with DNA methyltransferase 3A (DNMT3A)-mutant acute myeloid leukemia (AML) treated with chemotherapy agents, targeted therapy is highly desirable, calling for an extensive study on the effect of DNMT3Amutations on the AML phenotype.
An article recently published in the journal Nature Communications highlighted the enrichment of cell adhesion-associated genes with DNMT3A-mutant AML cells and demonstrated the therapeutic efficiency of graphdiyne oxide in exhibiting anti-leukemia activity against DNMT3A-mutant AML cells.
The interactions of graphdiyne oxide with c-type mannose (MRC2) and integrin β2 (ITGB2) genes facilitated the adhesion and cellular uptake of graphdiyne oxide. Besides, the graphdiyne oxide was reported to disrupt the actin cytoskeleton by binding to actin, eventually resulting in cell apoptosis of cancer cells.
This study has confirmed the therapeutic efficiency and in vivo safety of graphdiyne oxide against DNMT3A-mutant AML cells, demonstrating that graphdiyne oxide is a promising candidate for treating DNMT3A-mutant AML patients.
Graphdiyne Oxide and DNMT3A-mutant AML
Graphdiyne is the most stable unnatural carbon allotrope. It has a two-dimensional (2D) planar network structure formed by inserting a diacetylene linkage between two benzene rings in the graphene structure. Graphdiyne has a bandgap of 0.46 electron volts and high carrier mobility at room temperature, making it a promising candidate for future nanoelectronics.
The unique characteristics, such as sp–sp2 carbon atoms, uniform pores, and highly π-conjugated structure of graphdiyne, provide promising potential for practical applications in gas separation, catalysis, water remediation, humidity sensors, and energy-related fields. Moreover, graphdiyne oxide nanosheets have remarkable electronic, mechanical, and thermal properties, enabling their application in energy storage, electrocatalysis, and biomedicine.
Clonal hematopoiesis (CH) is an undesirable age-associated augmentation of hematopoietic stem cells (HSCs) that causes hematological malignancies, including myelodysplastic syndrome and AML. Loss of the DNMT3A gene in murine HSCs increased the risk of AML due to DNA hypomethylation-mediated upregulation of HSC multipotency genes. Clinically, DNMT3A plays a crucial role in suppressing tumor growth in hematological malignancies. Hence, extensive knowledge of the biological functions of DNMT3A can help develop new strategies to target its mutation.
The current treatment for DNMT3A-mutant AML includes a combination of daunorubicin and cytarabine, which are DNA-damaging medications. However, daunorubicin is an anthracycline drug, and DNMT3A mutations impede nucleosome reconstruction and promote anthracycline resistance, indicating the need for alternative strategies to DNA-damaging chemotherapy.
DNA methyltransferase-based small molecule inhibitors, such as decitabine and 5-azacytidine, have been investigated for treating patients with DNMT3A-mutant AML that yielded conflicting outcomes, inhibiting the targets or signaling pathways. Despite decades of study and several attempts to develop small-molecule-based targeted treatments for DNMT3A-mutant AML, clinical results have been discouraging.
Graphdiyne Oxide Nanosheets Against DNMT3A-Mutant AML Cells
In the present study, comprehensive in vitro and bioinformatic analyses revealed that the biological pathways associated with cell adhesion were enriched in DNMT3A-mutant AML cells. Consequently, this study aimed to identify potential targets of DNMT3A-mutant AML cells.
Screening multiple carbon nanomaterials revealed that graphdiyne and its oxide strongly inhibited the growth of DNMT3A-mutant AML cells. Mechanistically, the graphdiyne oxide nanosheets showed good dispersion in the culture media and interacted with MRC2 and ITGB2, allowing the cellular uptake of graphdiyne oxide.
Additionally, the binding of graphdiyne oxide to actin disrupts the actin cytoskeleton by preventing actin polymerization, leading to AML cell death. The therapeutic potential of graphdiyne oxide against DNMT3A-mutant AML cells and in vivo safety was validated in the present study, demonstrating a new path toward graphdiyne oxide-based therapies.
Furthermore, graphdiyne oxide was anticipated to be an alternative to daunorubicin for treating DNMT3AR882-AML patients to combat chemoresistance and self-renewal of leukemia stem cells (LSCs). In addition, graphdiyne oxide was also eliminated in vivo and in vitro LSCs without affecting healthy hematopoietic cells, suggesting the efficiency of graphdiyne oxide in treating DNMT3A-mutant AML patients without affecting adjacent normal cells.
In summary, the present study validated that the graphdiyne oxide spared healthy cells while serving as a high selectivity therapeutic agent to treat DNMT3A-mutant AML cells. The interaction of graphdiyne oxide with MRC2 and ITGB2 facilitated their cellular uptake to induce a therapeutic effect.
Although previous studies have reported the potency of graphene oxide (GO) in inducing alterations in the actin cytoskeleton in lung cancer cells by binding to it, this study revealed that GO had no significant influence on cell survival or the actin cytoskeleton in AML cells.
Additional research on graphdiyne oxide pharmacokinetics, including its circulation in the blood for extended time and advancements in administration techniques, is necessary for clinical applications. Nevertheless, this study has provided crucial information regarding the anti-leukemia potency of graphdiyne oxide in treating DNMT3A-mutant AML.
Wang, Q et al. (2022) Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells. Nature Communications. https://www.nature.com/articles/s41467-022-33410-w