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Dear Colleagues,

The last 4–5 years have ushered in a new era in acute myeloid leukemia therapy, with the advent and approval of multiple targeted therapies. Additionally, an improved understanding of the immune system in patients with hematologic malignancies has resulted in major progress in the development of immune therapies for the treatment of patients with AML, including monoclonal antibodies with or without conjugated toxins (bacterial or chemical), bispecific T-cell engagers and DART antibodies, immune-checkpoint-based therapies, and CAR-T cell approaches.

At the same time, there is an increasing understanding of AML tumor biology, creating the rationale for new combinations of drugs and new therapy development.

The numerous ongoing trials evaluating these novel therapies, with well-designed correlative interrogations of the immune system in patients treated in such trials, will further enhance our understanding of immune therapies as single-agent and combination approaches for the treatment of AML.

This Special Issue aims to focus on novel agents and their combinations. Focus will be placed on the efficacy of novel therapeutics and promising combination approaches to further improve outcomes in the treatment of patients with AML. We welcome the submission of original research articles and reviews.

Dr. Giovanni Martinelli
Dr. Claudio Cerchione
Guest Editors

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Keywords

acute myeloid leukemia
novel agents
target therapy

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18 pages, 5846 KiB

Open AccessArticle

Targeting EZH2 Promotes Chemosensitivity of BCL-2 Inhibitor through Suppressing PI3K and c-KIT Signaling in Acute Myeloid Leukemia

by Chan Yang, Yan Gu, Zheng Ge and Chunhua Song

Int. J. Mol. Sci. 2022, 23(19), 11393; https://doi.org/10.3390/ijms231911393 - 27 Sep 2022

Cited by 1 | Viewed by 1957

Abstract

Acute myeloid leukemia (AML) is one of the most common hematological malignancies with high heterogeneity, characterized by a differentiating block at the early progenitor stage. The selective BCL-2 inhibitor, Venetoclax (Ven), has shown exciting clinical results in a certain group of AML patients. However, Ven alone is insufficient to reach an enduringly complete response, which leads to the concern of Ven resistance. Alternative combined therapies with Ven are demanded in AML. Here, we reported the synergistic effect and molecular mechanism of the enhancer of zeste homolog 2 (EZH2) inhibitor DZNeP with Ven in AML cells. Results showed that the combination of DZNeP with Ven significantly induces cell proliferation arrest compared to single-drug control in AML cells and primary samples, and CalcuSyn analysis showed their significant synergy. The combination also significantly promotes apoptosis and increases the expression of pro-apoptotic proteins. The whole transcriptome analysis showed that phosphoinositide-3-kinase-interacting protein1 (PIK3IP1), the PI3K/AKT/mTOR signaling suppressor, is upregulated upon DZNeP treatment. Moreover, EZH2 is upregulated but PIK3IP1 is downregulated in 88 newly diagnosed AML cohorts compared to 70 healthy controls, and a higher expression of EZH2 is associated with poor outcomes in AML patients. Particularly, the combination of DZNeP with Ven dramatically eliminated CD117 (c-KIT) (+) AML blasts, suggesting the effect of the combination on tumor stem cells. In summary, our data indicated that DZNeP increases the sensitivity of Ven in AML by affecting PI3K and c-KIT signaling in AML. Our results also suggested that the therapeutic targeting of both EZH2 and BCL-2 provides a novel potential combined strategy against AML. Full article

(This article belongs to the Special Issue Novel Agents and Mechanisms in Acute Leukemias 2.0)

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