GADD45A: a key tumor suppressor in AML subtypes

In this issue of Blood, Hassan et al¹ have identified GADD45A as a pivotal tumor suppressor that acts as a key downstream target of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4), which governs the self-renewal capacity and therapy resistance of LGR4/HOXA9-dependent acute myeloid leukemia (AML) stem cells (LSCs). This finding suggests a potential novel therapeutic avenue for targeting LSCs in LGR4/HOXA9-dependent AML by restoring GADD45A expression.

AML is a clonal malignancy originating from LSCs and characterized by heterogeneous chromosomal abnormalities.^2,3 Although significant advancements have been achieved in AML treatment over the past decades, a substantial portion of patients are resistant to treatment or relapse due to the inadequacy of current therapies to effectively eliminate LSCs.⁴ Therefore, the identification of new signaling pathways that regulate the self-renewal and stemness of heterogeneous LSCs is significant and has the potential to revolutionize AML treatment.

Wang’s previous work demonstrated that LGR4 regulates the self-renewal and stemness of LSCs by controlling the p-PKAc/p-CREB/CBP-p300/β-catenin signaling pathway.⁵ In this study, the researchers further identified Gadd45a, a known negative regulator of the Wnt signaling,⁶ as a critical downstream target of LGR4 in MLL-AF9-transformed LSCs. The results showed that LGR4 negatively regulates Gadd45a expression through the p-PKAc-FOXO3A signaling axis. The authors demonstrate the critical role of GADD45A in LGR4-mediated leukemogenesis and elucidate its underlying mechanisms. They report 3 major discoveries underlying GADD45A loss-mediated AML leukemogenesis: (1) GADD45A loss facilitates self-renewal and stemness of LSCs through 2 primary mechanisms, first by activating the Wnt signaling via GSK3β inactivation and second by inhibiting the reactive oxygen species (ROS) levels; (2) GADD45A loss confers LSCs ferroptosis resistance by upregulating FTH1-mediated antioxidant defense; and (3) GADD45A loss induces replication stress and substantial mutations in genes involved in DNA repair, self-renewal, and DNA methylation. These new findings suggest GADD45A controls the self-renewal and drug resistance of LSCs through multiple mechanisms (see figure). Ferroptosis is a form of regulated cell death that relies on iron-induced lipid peroxidation.⁷ Several ferroptosis-inducing agents have been investigated for their potential use in AML treatment.^8,9 AML cells display varying degrees of susceptibility to ferroptosis induction, yet the underlying mechanism for this variability remains elusive. The discovery of GADD45A loss as a critical regulator of ferroptosis introduces a novel molecular pathway contributing to ferroptosis resistance in certain AML subsets. Concurrently, this research suggests the therapeutic strategy for LGR4/HOXA9-dependent AML of combining ferroptosis induction with the reestablishment of GADD45A expression.

What further studies does this study suggest? GADD45A loss diminishes the ROS levels, facilitating both the self-renewal and ferroptosis resistance in LSCs. Nevertheless, the results also reveal that GADD45A loss triggers genomic instability and mutations by elevating the DNA replication stress-induced ROS levels. How the LSCs perceive, synchronize, and reconcile these opposing ROS levels warrants further investigation. The authors suggested that LGR4-induced ROS could potentially inhibit GADD45A expression by increasing the activity or expression of DNA methyltransferases, as evidenced by induction of GADD45A expression on treatment with a DNA methyltransferase (DNMT) inhibitor in MLL-AF9-induced LSCs. Notably, some oncogenes are known to elevate intracellular ROS, raising the possibility that additional disease-driving oncogenes in AML might also downregulate GADD45A. It would be intriguing to investigate whether other AML-associated oncogenes regulate GADD45A expression and to explore the applicability of the current findings to other AML subtypes. What are the strategies for targeting GADD45A in AML cells? A previous study¹⁰ suggests that GADD45A can be silenced by DNA methylation at its promoter regions. Therefore, future investigation could explore whether combining DNA methyltransferase inhibitors together with the ferroptosis inducer RSL3 could effectively treat patients with AML, particularly those with low expression of GADD45A.

Conflict-of-interest disclosure: The authors declare no competing financial interests.