Low Expression of CD5 and CD6 Is Associated with Poor Overall Survival for Patients with T-Cell Malignancies.

Background: T-cell malignancies (TCMs), including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are highly aggressive and have a poor prognosis. To further understand prognostic stratifications and to design targeted therapies, this study aims to explore novel, potential biomarkers based on alterations in immune costimulatory molecules (CMs) for TCMs. Methods: Peripheral blood from 25 de novo T-ALL patients in our clinical center and transcriptome data from 131 to 162 patients with peripheral TCL (PTCL) from the GSE19069 and GSE58445 dataset, respectively, were obtained to assess the expression levels of CMs and their prognostic significance. Results: Seven CMs were associated with overall survival (OS). Among these CMs, CD5 and CD6 had the highest pairwise positive correlation (R = 0.69). CD5 and CD6 were significantly down-regulated in TCM patients compared with healthy individuals (HIs), and lower CD5 and CD6 expression was associated with poor OS for both T-ALL and TCL patients, particularly for patients greater than 60 years old. Furthermore, CD5 was positively correlated with CD6 in TCM patients. Compared with patients who were CD5highCD6high, T-ALL and TCL patients who were CD5lowCD6low had poor OS. Importantly, CD5highCD6high was an independent prognostic predictor for OS in T-ALL (HR = 0.39, 95% CI: 0.23-0.65, P < 0.001) and TCL (HR = 0.35, 95% CI: 0.19-0.62, P < 0.001) patients. Conclusions: Low expression of CD5 and CD6 was associated with poor OS for TCM patients, and this may be a potential immune biomarker panel for prognostic stratification of TCM patients.

Anticancer effects of disulfiram in T-cell malignancies through NPL4-mediated ubiquitin-proteasome pathway.

T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T-cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T-cell cell lines and primary T-ALL cells. We provide evidence that DSF exerts anticancer activity in T-cell malignancies by targeting the NPL4-mediated ubiquitin-proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin-proteasome pathway genes, anaphase-promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non-ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T-ALL (p < 0.05). More importantly, the weighted combination of NPL4, ANAPC1, and PSMD2 could visually display the 1-, 3-, and 5-year OS rates for patients with T-cell malignancies in a nomogram model and facilitate risk stratification. Specifically, risk stratification was an independent predictor of OS for patients with T-cell malignancies. In conclusion, DSF might induce apoptosis and inhibit the proliferation of malignant T-cells via the NPL4-mediated ubiquitin-proteasome pathway and offer a potential therapeutic option for T-cell malignancies.

Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice.

There is increasing clinical evidence to suggest a suppressive effect on hematopoiesis in myelodysplastic syndrome patients with iron overload. However, how iron overload influences hematopoiesis in myelodysplastic syndrome (MDS) remains unknown. Here, the RUNX1S291fs-transduced bone marrow mononuclear cells were yielded and transplanted into lethally irradiated recipient mice together with radioprotective bone marrow cells to generate MDS mice. Eight weeks post transplantation, the recipient mice received an intraperitoneal injection of 0.2 mL iron dextran at a concentration of 25 mg/mL once every other day for a total of 8 times to establish an iron overload model. In the present study, we show that iron overload impairs the frequency and colony-forming capacity of normal hematopoietic stem and progenitor cells, especially in erythroid, in MDS mice, which is due, at least in part, to growth differentiation factor 11-induced reactive oxygen species, shortening survival of MDS mice. Given that we are the first to construct an iron overload model in MDS mice, we hope this model will be helpful for further exploring the influence and mechanism of iron overload on MDS.

[Expression and Significance of HIF-1α in Erythropoiesis of Secondary Iron Overload Disease after Irradiation Damage].

OBJECTIVE: To study the expression of hypoxia inducible factor 1α(HIF-1α) of iron-overloaded in irradiated mice and its effect on erythropoiesis. METHODS: Twenty mice were randomly divided into 4 groups: Ctrl (control group), IR (irradiation group), IO (irradiation + iron overload group), and RAPA (rapamycin treatment group). The iron overload model was verified. The CFU-E (colony forming unit-erythroid) and BFU-E(burst colony forming unit-erythroid) were cultured; flow cytometry was used to detect the ratios of early stage (Ter119+CD71-) to late stage (Ter119+CD71+) of primitive erythroblasts; RT-PCR was used to detect the mRNA expression of HIF-1α and its related signal molecules in bone marrow cells. RESULTS: The expression of HIF-1α in IR and IO group was significantly higher than that in Ctrl group, and that in IO group was significantly higher than IR group (P<0.05). The ratio of late stage primitive erythroblasts, the number of CFU-E and BFU-E in both IR and IO group were lower than those in Ctrl group, and those in IO group were significantly lower than those in IR group (P<0.05). Compared with Ctrl group, the expression of HIF-1α related signal pathway molecules in both IR and IO group was significantly decreased (P<0.05). Compared with IO group, the expression of HIF-1α and its related signal molecules in RAPA(mTOR inhibitor) group was decreased significantly (P<0.05), the number of BFU-E was increased significantly(P<0.05). CONCLUSION: Irradiation induces the increase of HIF-1α and the decrease of the ability of hematopoietic colony formation and the ratio of late stage primitive erythroblasts. Iron overload can aggravate the injury. mTOR inhibitor rapamycin can partially alleviate the injury, suggesting that iron overload can lead to injury of erythropoiesis through HIF-1α.