m5C methylation modification guides the prognostic value and immune landscapes in acute myeloid leukemia.

The development, incidence, and metastasis of tumors are all intimately correlated with 5-methylcytosine (m5C). However, uncertainty surrounds the function of m5C in acute myeloid leukemia (AML). In this study, multicenter AML data were collected and analyzed comprehensively to grasp the gene expression level, clinicopathological characteristics, prognostic significance of m5C in AML and its relationship with the tumor microenvironment (TME). The m5C gene-mediated scoring system (m5CSS) was created using principal component analysis, and multiple cox regression analyses were utilized to determine the prognostic relevance of the m5C score. The investigation of the correlation among m5C, immune characteristics, clinical characteristics, immune infiltration level, as well as drug reaction at immune checkpoints, and immunotherapy efficacy confirmed that the change of the characteristics of immune cell infiltration and patient prognosis are linked with the m5C gene. Moreover, the m5CSS was employed to assess the pattern of m5C modification. Further analyses showed that the m5C score can served as a reliable indicator of AML prognosis. Crucially, the prognostic value of the m5C score was validated in terms of drug resistance and immunotherapy. This work reveals that AML diversity and the generation of complex TMEs are both impacted by m5C modifications. Therefore, understanding the m5C modification pattern will improve grasp of TME infiltration characteristics and assist exploring more efficient immunotherapeutic approaches.

The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression.

N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myelogenous leukemia (AML). Identification of the key regulators of m6A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for patients with AML. Here, we report overexpression of YTHDF1, an m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Whereas YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m6A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m6A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m6A-modified mRNAs, which might serve as a potential therapeutic target for AML. SIGNIFICANCE: The m6A reader YTHDF1 is required for progression of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.

Abnormal immune function of MDSC and NK cells from chronic phase CML patients restores with tyrosine kinase inhibitors.

BACKGROUND: Myeloid-derived suppressor cell (MDSC) -mediated immune suppression, and natural killer (NK) and/or T cell-mediated immune responses play important roles in Chronic myeloid leukemia (CML). However, detailed regulation mechanisms of these immune cells in CML have not been fully elucidated. METHODS: The proportion of MDSCs and effector NK cells in newly diagnosed CML patients, patients during TKI treatment, and healthy donors (HD) were detected using flow cytometry. Serum levels and mRNA expression of Arg1 and iNOS in newly diagnosed CML patients, patients during TKI treatment, and HD were measured by ELISA and qPCR, respectively. Effect of CML serum or peripheral blood mononuclear cells (PBMCs) on HD derived CD3+ T cell proliferation was evaluated by CFSE-labeled HD CD3+ T cells co-cultured with PBMCs and serum from CML patients. Effect of CML serum on NK cells killing activity was evaluated via detecting apoptosis of K562 cells. RESULTS: Proportion of Gr-MDSCs and the serum levels of Arg1 and iNOS were significantly increased in patients at diagnosis, and reduced following TKI treatment. However, the proportion of effector NK cells were decreased in patients at diagnosis, and increased following TKI treatment. Serum and PBMC from CML patients suppressed HD derived T cell proliferation in vitro. Additionally, serum from CML patients enhanced HD derived NK cell killing activity in vitro, while the addition of Arg1 inhibitor to CML serum suppressed this phenomenon. CONCLUSIONS: Gr-MDSCs and effector NK cells play an important role in the pathogenesis of CML, inhibiting the function of MDSC and restoring the function of NK cells is expected to be a therapeutic strategy for CML.

Cellular immune dysregulation in the pathogenesis of immune thrombocytopenia.

: Immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease characterized by immune-mediated increased platelet destruction and decreased platelet production, resulting from immune intolerance to autoantigen. The pathogenesis of ITP remains unclear, although dysfunction of T and B lymphocytes has been shown to be involved in the pathogenesis of ITP. More recently, it is found that dendritic cells, natural killer, and myeloid-derived suppressor cells also play an important role in ITP. Elucidating its pathogenesis is expected to provide novel channels for the targeted therapy of ITP. This article will review the role of different immune cells in ITP.

The Neuropilin-1 Ligand, Sema3A, Acts as a Tumor Suppressor in the Pathogenesis of Acute Leukemia.

Semaphorin-3A (Sema3A) and vascular endothelial growth factor (VEGF165) are ligands of neuropilin-1 (NRP-1 or CD304) and are related to immunoregulation and tumor angiogenesis, respectively. However, possible interactions between NRP-1 and Sema3A and VEGF165 in acute leukemia remain unclear, especially whether Sema3A plays a role in acute leukemia. In this study, both of the proportion of regulatory T cells (Tregs) and their expression of NRP-1 were found to increase in acute leukemia patients compared with healthy controls. In contrast, lower mRNA and plasma levels of Sema3A were detected in the acute leukemia patients. In vitro, the addition of exogenous Sema3A inhibited the expression of NRP-1 on Tregs and it promoted apoptosis of leukemia cells. However, in the presence of anti-Sema3A antibody, the effect of rhSema3A on NRP-1 expression was reversed. These results suggest that Sema3A promotes apoptosis in leukemia cells by inhibiting expression of NRP-1, and thus, represents a tumor suppressor protein with a role in the pathogenesis of acute leukemia. Consequently, NRP-1/Sema3A signaling may represent a novel target for the treatment of acute leukemia and should be further studied. Anat Rec, 302:1127-1135, 2019. © 2018 Wiley Periodicals, Inc.