The annual number of human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) is increasing steadily. Comparative studies about haplo-HCT versus HCT with HLA-matched sibling donors (MSD-HCT) have been tried in acute myeloid leukemia and B-cell acute lymphoblastic leukemia/lymphoma (ALL). Few studies were reported in adult T-cell ALL (T-ALL). In this retrospective study, a total of 88 consecutive patients with T-ALL were enrolled who underwent MSD-HCT (n = 24) and haplo-HCT (n = 64) with antithymocyte globulin (ATG)-based graft versus host disease (GVHD) prophylaxis between 2010 and 2022. Median follow-up for survivors was similar (43.5 [range: 7-88] months for MSD-HCT versus 43.5 (range: 6-144) months in the Haplo-HCT group). The 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD) was similar, 33% (95% confidence interval [CI], 16%-52%) after MSD-HCT versus 44% (95% CI, 31%-55%) after haplo-HCT, P = 0.52. The cumulative incidences of grade III-IV aGVHD were 8% (95% CI, 1%-23%) in the MSD-HCT group and 5% (95% CI, 1%-12%) in the haplo-HCT group (P = 0.50). The 2-year cumulative incidence of chronic GVHD (limited and extensive) in the haplo-HCT, 11% (95% CI, 5%-20%) was significantly lower than that in the MSD-HCT group (42% [95% CI, 21%-62%], P = 0.002). The cumulative incidence of 4-year relapse rates (44% versus 37%, P = 0.56) and non-relapse mortality (7% versus 21%, P = 0.08) did not differ between these two groups. There were also no differences in 4-year overall survival (46% versus 47%, P = 0.44) and progression-free survival (49% versus 42%, P = 0.45) between these two groups. On multivariate analysis, using busulfan/fludarabine (BU/Flu) conditioning regimen was found to be associated with worse clinical outcome. Our results suggested that ATG-based haplo-HCT platform could work as an alternative to MSD-HCT for adult patients with T-ALL. Compared with MSD-HCT, haplo-HCT might carry a low risk for cGVHD.

T-cell acute lymphoblastic leukemia (T-ALL), a heterogeneous hematological malignancy, is caused by the developmental arrest of normal T-cell progenitors. The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease. In this study, we performed multi-omics integration analysis, which included mRNA expression, chromatin accessibility, and gene-dependency database analyses, to identify potential stage-specific druggable targets and repositioned drugs for this disease. This multi-omics integration helped identify 29 potential pathological genes for T-ALL. These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle, hematopoietic stem cell differentiation, and the AMPK signaling pathway. Of these, four known druggable targets (CDK6, TUBA1A, TUBB, and TYMS) showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL. The TUBA1A expression level was higher in the early T cell precursor (ETP)-ALL cells, while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage. CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naïve to maturation stages. Furthermore, mebendazole and gemcitabine, which target TUBA1A and TYMS, respectively, exerted stage-specific inhibitory effects on T-ALL cell lines, indicating their potential stage-specific antileukemic role in T-ALL. Collectively, our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.

The present study aimed to investigate the anti-leukemic effects of dihydroartemisinin (DHA) on T-cell acute lymphoblastic leukemia (T-ALL) cell lines, Jurkat and Molt-4, and the underlying mechanisms. Cell Counting Kit-8 was performed to measure cell viability. Cell apoptosis and cell cycle distribution were assessed by flow cytometry. The expression levels of ATF4 and CHOP mRNA were assessed by reverse transcription-quantitative PCR, while the protein abundance of SLC7A11, GPX4, ATF4 and CHOP was determined by western blotting. Moreover, malondialdehyde, glutathione (GSH) and reactive oxygen species (ROS) assays were used to detect the levels of ferroptosis. The results showed that DHA suppressed T-ALL cell viability in vitro, and induced cell cycle arrest at S or G2/M phase. DHA also induced ROS burst, activated endoplasmic reticulum (ER) stress, disrupted the system Xc--GSH-GSH peroxidase 4 antioxidant system, and increased lipid peroxide accumulation, resulting in cell death. By contrast, the pharmacological inhibition of ferroptosis alleviated DHA-induced cell death, confirming that DHA induces T-ALL cell death via ferroptosis. Mechanistically, the effect of DHA on ferroptosis was partly mediated by downregulating SLC7A11 and upregulating the ATF4-CHOP signaling pathway, which is associated with ER stress. These results indicated that DHA may induce ferroptosis in T-ALL cell lines and could represent a promising therapeutic agent for treating T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic heterogeneous disease. This study explored the mechanism of specificity protein 1/3 (Sp1/3) in T-ALL cells through β-catenin by acting as targets of miR-495-3p. Expression levels of miR-495-3p, Sp1, Sp3, and β-catenin in the serum from T-ALL children patients, healthy controls, and the T-ALL cell lines were measured. The cell proliferation ability and apoptosis rate were detected. Levels of proliferation-related proteins proliferating cell nuclear antigen (PCNA)/cyclinD1 and apoptosis-related proteins B-cell lymphoma-2 associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) were determined. The binding of Sp1/3 and β-catenin promoter and the targeted relationship between miR-495-3p with Sp1/3 were analyzed. Sp1/3 were upregulated in CD4+ T-cells in T-ALL and were linked with leukocyte count and risk classification. Sp1/3 interference prevented proliferation and promoted apoptosis in T-ALL cells. Sp1/3 transcription factors activated β-catenin expression. Sp1/3 enhanced T-ALL cell proliferation by facilitating β-catenin expression. miR-495-3p targeted and repressed Sp1/3 expressions. miR-495-3p overexpression inhibited T-ALL cell proliferation and promoted apoptosis. Conjointly, Sp1/3, as targets of miR-495-3p limit apoptosis and promote proliferation in T-ALL cells by promoting β-catenin expression.

BACKGROUND: Identifying patients with high-risk T-cell acute lymphoblastic leukemia (T-ALL) is crucial for personalized therapy; however, the lack of robust biomarkers hinders prognosis assessment. To address this issue, our study aimed to screen and validate genes whose expression may serve as predictive indicators of outcomes in T-ALL patients while also investigating the underlying molecular mechanisms.
METHODS: Differentially expressed genes (DEGs) between T-ALL patients and healthy controls were identified by integrating data from three independent public datasets. Functional annotation of these DEGs and protein-protein interactions were also conducted. Further, we enrolled a prospective cohort of T-ALL patients (n = 20) at our center, conducting RNA-seq analysis on their bone marrow samples. Survival-based univariate Cox analysis was employed to identify gene expressions related to survival, and an intersection algorithm was sequentially applied. Furthermore, we validated the identified genes using cases from the Therapeutically Applicable Research to Generate Effective Treatments database, plotting Kaplan-Meier curves for secondary validation.
RESULTS: Through the integration of survival-related genes with DEGs identified in T-ALL, our analysis revealed six T-ALL-specific genes, the expression levels of which were linked to prognostic value. Notably, the independent prognostic value of SLC40A1 and TES expression levels was confirmed in both an external cohort and a prospective cohort at our center.
CONCLUSIONS: In summary, our preliminary study indicates that the expression levels of TES and SLC40A1 genes show promise as potential indicators for predicting survival outcomes in T-ALL patients.

BACKGROUND: Acute T lymphoblastic leukemia (T-ALL) occurs in 25% of adults diagnosed with Acute lymphocytic leukemia (ALL), and drug resistance is still a clinical obstacle. Augmenter of liver regeneration (ALR) is important to ALL drug resistance and is involved in the regulation of mitochondrial function; we speculated that the high expression of ALR in T-ALL promotes drug resistance through the alteration of mitochondrial function and the inhibition of the mitochondrial apoptosis pathway.
METHODS: We silenced and overexpressed ALR in the T-ALL cell lines that were untreated or treated with dexamethasone (DXM) or methotrexate (MTX). Apoptosis, proliferation, reactive oxygen species and ATP productions, mitochondrial membrane potential, and mitochondrial respiratory chain complex expression in cells were examined. The data were collated to comprehensively evaluate the effects of ALR expression change on mitochondrial function and drug resistance in T-ALL cells.
RESULTS: ALR knockdown led to the inhibition of proliferation, an increase in apoptosis, and the promotion of the cells\' sensitivity to drugs. It also showed mitochondrial dysfunction. ALR knockdown actived the mitochondrial apoptosis pathway. The treatment of ALR knockdown T-ALL cells with MTX or DXM further altered the mitochondrial function of T-ALL cells and actived the mitochondrial apoptosis pathway. Overexpression of ALR promoted cell proliferation and drug resistance, reduced apoptosis, protected mitochondrial function, and inhibited the mitochondrial apoptosis pathway.
CONCLUSIONS: T-ALL resistance caused by ALR through the alteration of mitochondrial function is associated with the inhibition of the mitochondrial apoptosis pathway.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous and aggressive subtype of hematologic malignancy, with limited therapeutic options due to the complexity of its pathogenesis. Although high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation have improved outcomes for T-ALL patients, there remains an urgent need for novel treatments in cases of refractory or relapsed disease. Recent research has demonstrated the potential of targeted therapies aimed at specific molecular pathways to improve patient outcomes. Chemokine-related signals, both upstream and downstream, modulate the composition of distinct tumor microenvironments, thereby regulating a multitude of intricate cellular processes such as proliferation, migration, invasion and homing. Furthermore, the progress in research has made significant contributions to precision medicine by targeting chemokine-related pathways. This review article summarizes the crucial roles of chemokines and their receptors in T-ALL pathogenesis. Moreover, it explores the advantages and disadvantages of current and potential therapeutic options that target chemokine axes, including small molecule antagonists, monoclonal antibodies, and chimeric antigen receptor T-cells.

T-cell acute lymphoblastic leukemia (T-ALL) is one of the deadliest and most aggressive hematological malignancies, but its pathological mechanism in controlling cell survival is not fully understood. Oculocerebrorenal syndrome of Lowe is a rare X-linked recessive disorder characterized by cataracts, intellectual disability, and proteinuria. This disease has been shown to be caused by mutation of oculocerebrorenal syndrome of Lowe 1 (OCRL1; OCRL), encoding a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase involved in regulating membrane trafficking; however, its function in cancer cells is unclear. Here, we uncovered that OCRL1 is overexpressed in T-ALL cells, and knockdown of OCRL1 results in cell death, indicating the essential role of OCRL in controlling T-ALL cell survival. We show OCRL is primarily localized in the Golgi and can translocate to plasma membrane (PM) upon ligand stimulation. We found OCRL interacts with oxysterol-binding protein-related protein 4L, which facilitates OCRL translocation from the Golgi to the PM upon cluster of differentiation 3 stimulation. Thus, OCRL represses the activity of oxysterol-binding protein-related protein 4L to prevent excessive PI(4,5)P2 hydrolysis by phosphoinositide phospholipase C β3 and uncontrolled Ca2+ release from the endoplasmic reticulum. We propose OCRL1 deletion leads to accumulation of PI(4,5)P2 in the PM, disrupting the normal Ca2+ oscillation pattern in the cytosol and leading to mitochondrial Ca2+ overloading, ultimately causing T-ALL cell mitochondrial dysfunction and cell death. These results highlight a critical role for OCRL in maintaining moderate PI(4,5)P2 availability in T-ALL cells. Our findings also raise the possibility of targeting OCRL1 to treat T-ALL disease.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy derived from T cells. Numerous CAR T therapies have been successfully applied to treat hematologic malignancies in the clinic. Nevertheless, there remain several challenges to the extensive application of CAR T cell therapy in T cell malignancies, especially in T-ALL. The main reason for CAR T therapy limitations is that T-ALL cells and normal T cells share antigens, which improves the difficulty of sorting pure T cells, resulting in product contamination, and would lead to CAR T cell fratricide. Thus, we considered creating a CAR on T-ALL tumor cells (CAR T-ALL) to prevent fratricide and eliminate tumor cells. We found that T-ALL cells transduced with CAR would actually commit fratricide. However, CAR T-ALL could kill only tumor cells on T-ALL cell lines, and other types of tumor cells had no killing function after being transferred with CAR. Furthermore, we created CD99 CAR with expression controlled by the Tet-On system on Jurkat cells, which could avoid the fratricide of CAR T-ALL during proliferation, ensuring the controllability of the killing time and effect. Jurkat transduced with a CAR-targeting antigen, which was expressed on other cancer cells, could kill other cancer cell lines, demonstrating that T-ALL cells could be used as tool cells for cancer therapy. Our study supplied a new feasible treatment regimen for cancer treatment in the clinic.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) has historically been associated with a poor prognosis. However, prognostic indicators and methods of treatment used for T-ALL remain controversial. A total of 136 children newly diagnosed with T-ALL between 2005 and 2018 were consecutively enrolled in this study. We assessed the effect of different prognostic factors, such as clinical characteristics, minimal residual disease (MRD), and the role of transplantation in postremission treatment, as the outcomes. Compared with B-ALL patients, patients with T-ALL are generally older, more likely to be male and have a higher white blood cell count. The complete remission (CR) rate was 95.6%, while the 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 74.3 ± 3.7%, 71.3 ± 3.9%, and 24.4 ± 3.8%, respectively. In the multivariate analysis, day 33 MRD ≥0.1% and hyperleukocytosis were associated with a significantly worse prognosis in the whole group. Transplantation resulted in a significant survival advantage, compared with chemotherapy, for high-risk (HR) patients (5-year CIR: 15.6 ± 10.2% vs. 55.6 ± 11.7%, P = .029). The prognosis of children with T-ALL was poor, and the MRD on day 33 was found to be an important predictive factor of clinical outcome at our center.