Inhibition of NRF2 enhances the acute myeloid leukemia cell death induced by venetoclax via the ferroptosis pathway.

Venetoclax, an inhibitor that selectively targets B cell lymphoma-2 (BCL-2) that has been approved for treating adult acute myeloid leukemia (AML) in combination with hypomethylating agents. However, its short duration of response and emergence of resistance are significant issues. In this study, we found that the sensitivity of AML cells to venetoclax was considerably enhanced by ML385, an inhibitor of the ferroptosis factor nuclear transcription factor erythroid 2-related factor 2 (NRF2). Using AML samples, we verified that NRF2 and its target gene ferritin heavy chain 1 (FTH1) were highly expressed in patients with AML and correlated with poor prognosis. Downregulation of NRF2 could inhibit FTH1 expression and significantly enhance the venetoclax-induced labile iron pool and lipid peroxidation. By contrast, NRF2 overexpression or administration of the reactive oxygen species inhibitor N-acetylcysteine and vitamin E could effectively suppress the anti-AML effects of ML385+venetoclax. Furthermore, the ferroptosis inducer erastin increased the anti-AML effects of venetoclax. Our study demonstrated that NRF2 inhibition could enhance the AML cell death induced by venetoclax via the ferroptosis pathway. Thus, the combination of ML385 with venetoclax may offer a favorable strategy for AML treatment.

CD69 is a Promising Immunotherapy and Prognosis Prediction Target in Cancer.

Immunotherapy utilizing T cells that attack tumors is a promising strategy for treatment, but immune suppressive T cell subsets, such as regulatory T cell (Treg), and immune checkpoint molecules, including programmed death-1 (PD-1), can suppress the intensity of a T cell immune reaction and thereby impair tumor clearance. Cluster of differentiation 69 (CD69), known as an early leukocyte activation marker, can be used as a measure or early marker of T cell activation. In recent years, the functions of CD69 in the regulation of Treg/Th17 (T helper cell 17) differentiation and in the tissue retention of T cells have attracted considerable interest. These functions are related to the role of CD69 in immune suppression in tumor environments (TME). In this review, we first summarized current perspectives in the biological function of CD69 and demonstrated that CD69 acts as a regulator of T cell activation, differentiation, retention, and exhaustion. Then, we discussed recent advances in understanding of CD69 deficiency and anti-CD69 antibody administration and shed light on the value of targeting on CD69 for cancer immunotherapy and prognosis prediction.

The regulation mode of RIN transcription factor involved in ethylene biosynthesis in tomato fruit.

BACKGROUND: LE-RIN encodes the RIN (Ripening Inhibitor) transcription factor belonging to the MADS (Mcm1, Agamous, Deficiens, Srf) box family and regulates tomato ripening. The RIN transcription factor plays an indispensable role in ethylene biosynthesis. In the study, we respectively evaluated gene expressions and enzymatic activities of 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS) and ACC oxidase (ACO) and ethylene production to understand the transcriptional regulation of RIN transcription factor in ethylene biosynthesis. RESULTS: RIN transcription factor generates strong or weak induction of the expression of LE-ACS2, LE-ACS4 and LE-ACO1 associated with ethylene biosynthesis. Exogenous ethylene could positively affect gene expression of mature green AC tomato fruit compared with the control, including LE-ACS2, LE-ACO1 and LE-ACO4. However, LE-ACS6 expression was negatively affected by RIN transcription factor and high ethylene production. Accordingly, the activities of ACC synthase and ACC oxidase and ethylene production were also changed. CONCLUSION: RIN transcription factor has an impact upon ethylene biosynthesis via regulating transcription of LE-ACS2, LE-ACS4, LE-ACO1 and LE-ACS6. These results will help to further clarify the mechanism of tomato fruit development and ripening, and to maintain quality and prolong shelf life of tomato fruit.