SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.

High-Grade B-Cell Lymphoma With Malignant Effusions as the Initial Presentation.

OBJECTIVES: Malignant effusion is usually caused by metastatic carcinoma. Malignant lymphoma is often not included as a top differential diagnosis of malignant effusion. Here, we describe 3 cases of young female patients with no significant past medical history who presented with fluid overload and were diagnosed with high-grade B-cell lymphoma (HGBL). METHODS: We conducted histopathologic examination and immunophenotypic and cytogenetic analyses on three cases using immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), and karyotyping. We also included patients' clinical and radiological findings in our case reports. RESULTS: Histologic examination of the effusion samples showed numerous intermediate to large lymphoma cells with irregular nuclear contours and fine chromatin. The lymphoma cells were positive for CD10, CD20, BCL2, BCL6, and PAX5 and negative for CD34, cyclin D1, HHV-8, and TdT. In situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs was negative. The proliferation index by Ki-67 stain was more than 80%. Flow cytometry showed CD10-positive B cells with monotypic immunoglobulin light chain expression. Fluorescence in situ hybridization analysis demonstrated MYC, BCL2, or BCL6 rearrangements. These 3 patients were diagnosed as having HGBL with double-/triple-hit rearrangements. Despite receiving aggressive chemotherapy, all 3 patients had a dismal clinical course, with 2 patients dying less than 2 years after initial diagnosis. CONCLUSIONS: High-grade B-cell lymphoma should be considered in the differential diagnoses of malignant effusions. Flow cytometric and FISH analyses of the body fluid specimens are essential to reach an accurate and timely diagnosis.

Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis.

SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.

High-grade B-cell lymphoma (HGBL)-NOS is clinicopathologically and genetically more similar to DLBCL/HGBL-DH than DLBCL.

High-grade B-cell lymphoma, not otherwise specified (HGBL-NOS) is rare and data focused on these neoplasms is lacking. We studied the clinicopathologic and genetic features of 136 HGBL-NOS patients and compared them to patients with DLBCL/HGBL-DH (n = 224, defined by 5th Edition WHO) and DLBCL (n = 217). HGBL-NOS patients had clinical features similar to DLBCL/HGBL-DH patients. MYC rearrangement (MYC-R) was present in 43% of HGBL-NOS. With induction regimen similar to DLBCL/HGBL-DH patients, HGBL-NOS patients had a median overall survival (OS) of 28.9 months, similar to DLBCL/HGBL-DH (p = 0.48) but inferior to DLBCL patients (p = 0.03). R-EPOCH induction was associated with improved OS compared with R-CHOP. MYC-R, history of lymphoma, and high IPI were independent adverse prognostic factors in HGBL-NOS patients. Whole transcriptome profiling performed on a subset of HGBL-NOS cases showed a profile more similar to DLBCL/HGBL-DH than to DLBCL; 53% of HGBL-NOS had a DH-like signature (DH-like-Sig) and were enriched for MYC-R. DH-like-Sig+ HGBL-NOS patients had a poorer OS than DH-like-Sig-negative patients (p = 0.04). In conclusion, HGBL-NOS has clinicopathologic features and a gene expression profile more similar to DLBCL/HGBL-DH than to DLBCL. Cases of HGBL-NOS frequently carry MYC-R and have a DH-like-Sig+. R-EPOCH induction in HGBL-NOS appears associated with improved OS compared with standard R-CHOP.

Loss of SIRT1 inhibits hematopoietic stem cell aging and age-dependent mixed phenotype acute leukemia.

Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders and malignancies. SIRT1 has been implicated in healthy aging, but its role in HSC aging is poorly understood. Surprisingly, we found that Sirt1 knockout improved the maintenance of quiescence of aging HSCs and their functionality as well as mouse survival in serial bone marrow transplantation (BMT) recipients. The majority of secondary and tertiary BMT recipients of aging wild type donor cells developed B/myeloid mixed phenotype acute leukemia (MPAL), which was markedly inhibited by Sirt1 knockout. SIRT1 inhibition also reduced the growth and survival of human B/myeloid MPAL cells. Sirt1 knockout suppressed global gene activation in old HSCs, prominently the genes regulating protein synthesis and oxidative metabolism, which may involve multiple downstream transcriptional factors. Our results demonstrate an unexpected role of SIRT1 in promoting HSC aging and age-dependent MPAL and suggest SIRT1 may be a new therapeutic target for modulating functions of aging HSCs and treatment of MPAL.

TdT expression in acute myeloid leukemia with minimal differentiation is associated with distinctive clinicopathological features and better overall survival following stem cell transplantation.

The diagnostic criteria for acute myeloid leukemia (AML), not otherwise specified, with minimal differentiation (AML-M0, French-American-British classification), have been refined in the 2008 World Health Organization (WHO) classification. Terminal deoxynucleotidyl transferase (TdT) expression in AML-M0 has been proposed by others as a surrogate for RUNX1 (runt-related transcription factor 1) mutations, a mutation associated with distinct gene expression profiles in AML-M0. In this study, we investigated the significance of TdT expression in AML-M0 cases defined using the 2008 WHO classification criteria. Demographic, laboratory and clinical information were obtained from the hospital medical records. Statistical analysis was performed using Student's t-test, log-rank test and Fisher's exact test. The study group included 30 AML-M0 patients (male:female=19:11; median age: 60 years). In all, 10 cases of AML-M0 were positive for TdT(+) and 20 cases were negative for TdT(-). Patients with TdT+ AML-M0 had higher peripheral blood and bone marrow blast counts compared to patients with TdT- AML-M0 (P=0.01). TdT expression in AML-M0 was not associated with a distinct immunophenotype. Monoclonal IgH and TCR gene rearrangements were frequent, but independent of TdT expression in AML-M0. TdT expression in AML-M0 correlated with trisomy 13 and inversely correlated with aberrations of chromosomes 5 and 17. Among six patients with AML-M0 who received a stem cell transplant, overall survival was significantly longer for the three TdT+ patients compared with the three TdT- patients (P=0.03). In the TdT+AML-M0 subgroup, the three patients with stem cell transplant had better overall survival compared with five patients who did not receive stem cell transplant (P=0.01). We conclude that AML-M0, as currently defined in the 2008 WHO classification, can be divided into two groups based on TdT expression. Although there is a need to assess a greater number of patients, our results suggest that TdT positivity in AML-M0 identifies a subset of patients with a better prognosis after stem cell transplant.