Introduction

In June 2024, Blood Science published a groundbreaking study led by Dr. Hui Zeng and colleagues from the The First Affiliated Hospital of Jinan University , focusing on the role of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in acute myeloid leukemia (AML). AML is a severe hematological malignancy characterized by the rapid proliferation of immature white blood cells, leading to significant dysfunction in the blood and bone marrow. Despite advancements in treatment, relapsed and refractory (RR) AML continues to pose a significant clinical challenge with a poor prognosis, emphasizing the need for novel therapeutic targets to enhance patient outcomes.

The study conducted by Dr. Hui Zeng and the team investigates HMGCS1, a critical enzyme in the cholesterol biosynthesis pathway, and its potential as a therapeutic target in AML. The research reveals that HMGCS1 is overexpressed in RR AML patients and is associated with poorer overall survival (OS). Knockout (KO) experiments on HMGCS1 in AML cells showed reduced cell proliferation and increased sensitivity to chemotherapy, whereas overexpression (OE) of HMGCS1 had the opposite effects. The study also delves into the molecular mechanisms, particularly the involvement of the mitogen-activated protein kinase (MAPK) pathway in mediating these effects.

Study Design and Patient Population

The study employed a combination of clinical specimen analysis, animal models, and in vitro cell studies to investigate the role of HMGCS1 in AML. The research analyzed 257 complete remission (CR) and 78 RR AML bone marrow samples to compare lipid levels, revealing that RR patients exhibited significantly higher levels of total cholesterol (TC) and triglycerides (TG). Furthermore, 87 bone marrow samples from AML patients were used to validate the expression levels of HMGCS1, demonstrating significantly higher expression in RR patients compared to those in CR.

Key Findings

The study’s findings indicate that HMGCS1 plays a pivotal role in promoting leukemia cell growth and reducing chemotherapy sensitivity. Overexpression of HMGCS1 in AML cell lines led to increased cell proliferation and decreased sensitivity to chemotherapeutic agents, while knockout of HMGCS1 resulted in reduced cell growth and enhanced sensitivity to drugs like adriamycin (ADR). Additionally, the study found that HMGCS1 overexpression activated the MAPK pathway, a crucial signaling pathway involved in cell growth and survival, whereas its knockout suppressed this pathway.

Efficacy Outcomes

To further explore the therapeutic potential, the study tested hymeglusin, a specific inhibitor of HMGCS1, on AML cells. Treatment with hymeglusin decreased the viability of AML cells and enhanced their sensitivity to ADR and cytarabine (Ara-C). The combination of hymeglusin with these chemotherapeutic agents exhibited synergistic effects, significantly inhibiting AML cell growth. Moreover, hymeglusin showed minimal toxicity to normal hematopoietic stem and progenitor cells (HSPCs) at low concentrations, indicating its potential as a targeted therapy for AML.

Figure 1. Aberrant lipids level and HMGCS1 level in clinical AML samples.

(Blood Science 6(3):p e00192, July 2024. | DOI: 10.1097/BS9.0000000000000192)

Conclusion

The research led by Dr. Hui Zeng and colleagues provides critical insights into the role of HMGCS1 in AML and its potential as a therapeutic target. With a clear link between HMGCS1 overexpression and poor prognosis in RR AML patients, targeting HMGCS1 could offer a novel approach to restoring chemotherapy sensitivity and improving treatment outcomes in AML. These findings pave the way for future studies aimed at developing effective therapies targeting HMGCS1 in AML.