The gut microbiota has been linked to many cancers, yet its role in acute myeloid leukaemia (AML) progression remains unclear. Here, we show decreased diversity in the gut microbiota of AML patients or murine models. Gut microbiota dysbiosis induced by antibiotic treatment accelerates murine AML progression while faecal microbiota transplantation reverses this process. Butyrate produced by the gut microbiota (especially Faecalibacterium) significantly decreases in faeces of AML patients, while gavage with butyrate or Faecalibacterium postpones murine AML progression. Furthermore, we find the intestinal barrier is damaged in mice with AML, which accelerates lipopolysaccharide (LPS) leakage into the blood. The increased LPS exacerbates leukaemia progression in vitro and in vivo. Butyrate can repair intestinal barrier damage and inhibit LPS absorption in AML mice. Collectively, we demonstrate that the gut microbiota promotes AML progression in a metabolite-dependent manner and that targeting the gut microbiota might provide a therapeutic option for AML.

Circular RNAs (circRNAs) represent a widespread class of non-coding RNAs, which drew little attention in the past. Recently, limited data showed their promising future to act as biomarkers in human cancer, but the characteristics and functions remain largely unknown in hematopoietic malignancies, especially in leukemia. In this study, with the help of circRNA microarray, we demonstrated the expression profile of circRNAs in acute myeloid leukemia (AML) patients, and identified a large number of circRNAs possibly expressed in a leukemia specific manner. We also described a circRNA signature related to AML risk-status based on the bioinformatics prediction. In particular, a downregulated circRNA, hsa_circ_0004277, was characterized and functionally evaluated in a cohort of 115 human samples, thus offering a potential diagnostic marker and treatment target in AML. Interestingly, we found chemotherapy could significantly restore the expression of hsa_circ_0004277, indicating the increasing level of hsa_circ_0004277 was associated with successful treatment. Furthermore, a detailed circRNA–miRNA–mRNA interaction network was presented for hsa_circ_0004277, allowing us to better understand its underlying mechanisms for function in AML.

The NLRP3 inflammasome plays a pro-tumorigenic role in various malignancies. However, its potential role in lymphomagenesis remains unclear. In this study, we identified an immunosuppressive state in patients with diffuse large B cell lymphoma (DLBCL), which was characterized by markedly elevated interleukin (IL)-18 levels in lymphoma tissues and positive correlation with programmed death ligand 1 (PD-L1) expression. Furthermore, NLRP3 inflammasome activation in DLBCL cell lines upregulated PD-L1 and reduced the proportion of cytotoxic T cells. NLRP3 inflammasome blockade in vivo suppressed lymphoma growth and ameliorated anti-tumor immunity by downregulating PD-L1 in the tumor microenvironment and decreasing the proportion of PD-1/TIM-3-expressing T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Further in vivo studies revealed IL-18 as the main effector cytokine involved in the negative regulation of anti-lymphoma immunity. Interestingly, NLRP3 blockers combined with anti-PD-L1 treatment exerted antagonistic effects during lymphoma therapy. Altogether, our findings indicate that NLRP3 inflammasome promotes immunosuppression by modulating PD-L1 and immune cells. Accordingly, this study highlights the prognostic and therapeutic values of the NLRP3 inflammasome in lymphoma.

Background: Notch1 is a potent regulator known to play an oncogenic role in many malignancies including T-cell acute lymphoblastic leukemia (T-ALL). Tumor hypoxia and increased hypoxia-inducible factor-1α (HIF-1α) activity can act as major stimuli for tumor aggressiveness and progression. Although hypoxia-mediated activation of the Notch1 pathway plays an important role in tumor cell survival and invasiveness, the interaction between HIF-1α and Notch1 has not yet been identified in T-ALL. This study was designed to investigate whether hypoxia activates Notch1 signalling through HIF-1α stabilization and to determine the contribution of hypoxia and HIF-1α to proliferation, invasion and chemoresistance in T-ALL. Methods: T-ALL cell lines (Jurkat, Sup-T1) transfected with HIF-1α or Notch1 small interference RNA (siRNA) were incubated in normoxic or hypoxic conditions. Their potential for proliferation and invasion was measured by WST-8 and transwell assays. Flow cytometry was used to detect apoptosis and assess cell cycle regulation. Expression and regulation of components of the HIF-1α and Notch1 pathways and of genes related to proliferation, invasion and apoptosis were assessed by quantitative real-time PCR or Western blot. Results: Hypoxia potentiated Notch1 signalling via stabilization and activation of the transcription factor HIF-1α. Hypoxia/HIF-1α-activated Notch1 signalling altered expression of cell cycle regulatory proteins and accelerated cell proliferation. Hypoxia-induced Notch1 activation increased the expression of matrix metalloproteinase-2 (MMP2) and MMP9, which increased invasiveness. Of greater clinical significance, knockdown of Notch1 prevented the protective effect of hypoxia/HIF-1α against dexamethasone-induced apoptosis. This sensitization correlated with losing the effect of hypoxia/HIF-1α on Bcl-2 and Bcl-xL expression. Conclusions: Notch1 signalling is required for hypoxia/HIF-1α-induced proliferation, invasion and chemoresistance in T-ALL. Pharmacological inhibitors of HIF-1α or Notch1 signalling may be attractive interventions for T-ALL treatment.

Chemoresistant leukemia relapse is one of the most common causes of death for acute myeloid leukemia (AML) patients and the homing/engraftment in bone marrow (BM) are crucial steps for AML cells to acquire chemoresistance by interacting with stromal cell components. No crosstalk between m⁶A modification and homing/engraftment has been reported. Here, we performed comprehensive high-throughput analyses, including RNA sequencing of CR (complete remission) and relapsed AML patients, and reverse-phase protein arrays of chemoresistant cells to identify METTL3 as a key player regulating AML chemoresistance. Then, METTL3-mediated m⁶A modification was proved to induce the chemoresistance in vitro and in vivo. Furthermore, AML homing/engraftment was discovered being enhanced by upregulated-METTL3 in chemoresistant cells. And the homing/engraftment and drug-resistance associated phenotypes of chemoresistant cells could be reversed by a METTL3 inhibitor. Mechanistically, METTL3 extended the half-life of ITGA4 mRNA by m⁶A methylation, and then, increased expression of ITGA4 protein to enhance homing/engraftment of AML cells. The results provide insights into the function of m⁶A modification on the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant leukemia with extremely limited treatment for relapsed patients. N6‐methyladenosine (m⁶A) reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) participates in the initiation and growth of cancers by communicating with various targets. Here, we found IGF2BP2 was highly expressed in T-ALL. Gain and loss of IGF2BP2 demonstrated IGF2BP2 was essential for T-ALL cell proliferation in vitro and loss of IGF2BP2 prolonged animal survival in a human T-ALL xenograft model. Mechanistically, IGF2BP2 directly bound to T-ALL oncogene NOTCH1 via an m⁶A dependent manner. Furthermore, we identified a small-molecule IGF2BP2 inhibitor JX5 and treatment of T-ALL with JX5 showed similar functions as knockdown of IGF2BP2. These findings not only shed light on the role of IGF2BP2 in T-ALL, but also provide an alternative γ‑Secretase inhibitors (GSI) therapy to treat T-ALL.