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The stromal niche plays a pivotal role in AML chemoresistance and energy metabolism reprogramming is a hallmark of a tumor. 5′‐Adenosine monophosphate‐activated protein kinase (AMPK) is an important energy sensor suppressing mammalian target of rapamycin complex 1 (mTORC1) activity. However, the role of AMPK‐mTORC1 pathway on connecting AML cell energy metabolism reprogramming and chemoresistance induced by the bone marrow microenvironment (BMM) is not defined. Here, with a co‐culture system that simulates the interaction between BMM and AML cells, it is shown that stromal contact led to a decreased sensitivity to chemotherapy accompanied by an increase of oxidative phosphorylation (OXPHOS) activity and mitochondrial ATP synthesis in AML cells. The increased OXPHOS activity and excessive ATP production promoted chemoresistance of AML cells through inhibiting AMPK activity and in turn activating mTORC1 activity. In an in vivo AML mouse model, depletion of AMPK activity with genetic targeting promoted AML progression and reduced their sensitivity to chemotherapeutic drugs. Collectively, AML cells' acquired increased OXPHOS activity as well as AMPK inhibition could be therapeutically exploited in an effort to overcome BMM‐mediated chemoresistance. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. AML cells secrete angiogenic factors to remodel vasculature and acquire chemoresistance; however, antiangiogenic drugs are often ineffective in AML treatment. Cancer cell‐derived exosomes can induce angiogenesis, but their role in vascular remodeling during AML is unclear. Here, we found that exosomes secreted by AML cells promoted proliferation and migration and tube‐forming activity of human umbilical vein endothelial cells (HUVECs), whereas HUVECs conferred chemoresistance to AML cells. AML cell‐derived exosomes contained vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) messenger RNA and induced VEGFR expression in HUVECs. Furthermore, they enhanced glycolysis, which correlated with HUVEC proliferation, tube formation, and resistance to apoptosis. Thus, AML cells secrete VEGF/VEGFR‐containing exosomes that induce glycolysis in HUVECs leading to vascular remodeling and acquisition of chemoresistance. These findings may contribute to the development of novel therapeutic strategies targeting exosomes in AML. [ABSTRACT FROM AUTHOR]

Patients with acute myeloid leukaemia (AML) have poor prognoses and low overall survival (OS) rates owing to its heterogeneity and the complexity of its tumour microenvironment (TME). N6-methyladenosine (m 6 A) modification plays a key role in the initiation and progression of haematopoietic malignancies. However, the underlying function of m 6 A regulators in AML remains elusive. This study thoroughly analysed the m 6 A modification features of 177 AML patients based on 22 m 6 A regulators. Utilizing unsupervised clustering, we determined three distinct m 6 A modification patterns related to different biological functions, TME cell-infiltrating characteristics and clinical outcomes. Additionally, a risk score was constructed based on six m 6 A regulators-associated prognostic signatures and was validated as an independent and valuable prognostic factor for AML. Patients with a low-risk score exhibited better survival than those with a high-risk score. Many m 6 A regulators were aberrantly expressed in AML, among which METTL14, YTHDC2, ZC3H13 and RBM15 were observed to be associated with the OS of AML. In addition, these four m 6 A regulators were found to be noticeably related to the immune checkpoint inhibitor (ICI) treatments. Finally, we verified the expression levels of these four m 6 A regulators in AML and healthy samples and three groups of AML patients with different risk categories. Collectively, our study indicates that the m 6 A modification pattern is involved in TME immune-infiltrating characteristics and prognosis in AML. A better understanding of the m 6 A modification pattern will help enhance our knowledge of the molecular mechanisms of AML and develop potential prognosis prediction indicators and more effective immunotherapeutic strategies.

Objectives: Red blood cell distribution width (RDW) is a widely used clinical parameter recently deployed in predicting various cancers. This study aimed to evaluate the prognostic value of RDW in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: We conducted a retrospective study of 745 patients with HBV-related HCC, 253 patients with chronic hepatitis B (CHB), and 256 healthy individuals to compare their hematological parameters and analyze their RDW levels. Potential risk factors for long-term all-cause mortality in patients with HBV-related HCC were predicted using Multivariate Cox regression. A nomogram was generated, and its performance was evaluated. Results: The RDW of patients with HBV-related HCC was significantly higher than that of those with CHB and healthy controls. In the former, splenomegaly, liver cirrhosis, larger tumor diameter, multiple tumor number, portal vein tumor thrombus, and lymphatic or distant metastasis were significantly increased, and the later the Child-Pugh grade and Barcelona clinic liver cancer stage, the higher the RDW. Furthermore, multivariate Cox regression analysis identified RDW as an independent risk factor for predicting long-term all-cause mortality in patients with HBV-related HCC. Finally, we successfully generated a nomogram incorporating RDW and validated its predictive ability. Conclusions: RDW is a potentially valuable hematological marker for predicting the survival and prognosis of patients with HBV-related HCC. The nomogram incorporating RDW can be used as an effective tool to plan the individualized treatment of such patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)