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PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway.

ABSTRACT: Acute myeloid leukemia (AML) is a major hematopoietic malignancy characterized by the accumulation of immature and abnormally differentiated myeloid cells in bone marrow. Here with in vivo and in vitro models, we demonstrate that the Plant homeodomain finger gene 6 (PHF6) plays an important role in apoptosis and proliferation in myeloid leukemia. Phf6 deficiency could delay the progression of RUNX1-ETO9a and MLL-AF9-induced AML in mice. PHF6 depletion inhibited the NF-κB signaling pathways by disrupting the PHF6-p50 complex and partially inhibiting the nuclear translocation of p50 to suppress the expression of BCL2. Treating PHF6 over-expressed myeloid leukemia cells with NF-κB inhibitor (BAY11-7082) significantly increased their apoptosis and decreased their proliferation. Taken together, in contrast to PHF6 as a tumor suppressor in T-ALL as reported, we found that PHF6 also plays a pro-oncogenic role in myeloid leukemia, and thus potentially to be a therapeutic target for treating myeloid leukemia patients.

SUBMITTER: Hou S

PROVIDER: S-EPMC10400421 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway.

Hou Shuaibing S Wang Xiaomin X Guo Tengxiao T Lan Yanjie Y Yuan Shengnan S Yang Shuang S Zhao Fei F Fang Aizhong A Liu Na N Yang Wanzhu W Chu Yajing Y Jiang Erlie E Cheng Tao T Sun Xiaojian X Yuan Weiping W

Leukemia 20230701 8

Acute myeloid leukemia (AML) is a major hematopoietic malignancy characterized by the accumulation of immature and abnormally differentiated myeloid cells in bone marrow. Here with in vivo and in vitro models, we demonstrate that the Plant homeodomain finger gene 6 (PHF6) plays an important role in apoptosis and proliferation in myeloid leukemia. Phf6 deficiency could delay the progression of RUNX1-ETO9a and MLL-AF9-induced AML in mice. PHF6 depletion inhibited the NF-κB signaling pathways by di ...[more]

PMID: 37393343

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Project description:Objectives: Osteoarthritis (OA) is a joint disease characterized by degeneration of joint cartilage and is a significant cause of severe joint pain, physical disability, and impaired quality of life in the aging population. Celastrol, a Chinese herbal medicine, has attracted wide interests because of its anti-inflammatory effects on a variety of diseases. This study aimed to investigate the effect of celastrol on OA as well as the mechanisms in vivo and in vitro. Methods: A rat knee OA model was established using "medial collateral ligament transection (MCLT) + partial meniscectomy (pMMT)". Eight weeks after surgery, the OA rats started to receive intra-articular injection of celastrol (1 mg/kg) once a week. Safranin O-fast green (S&F) and hematoxylin and eosin (H&E) staining were used to estimate histopathological changes. Micro-CT was used to evaluate bone volume of the subchondral bone of the knee joint. Chondrocytes were isolated from the knee cartilage of rats and OA patients. Enzyme linked immunosorbent assay (ELISA), Western Blot (WB), Polymerase Chain Reaction (PCR), and Immunohistochemistry (IHC) were used to detect the expression of inflammatory factors and stromal proteins, respectively. Results: We found that celastrol treatment significantly delayed the progression of cartilage damage with a significant reduction in osteophyte formation and bone resorption in OA rat model. In IL-1β-stimulated rat chondrocytes, celastrol significantly suppressed the production of inflammatory factors such as cyclooxygenase-2 (COX2), interleukin-6 (IL-6), and prostaglandin E2 (PEG2), and reduced IL-1β-induced matrix degradation by down-regulating the expression of matrix metalloproteinase 13 (MMP13). In addition, we found that toll-like receptor 2 (TLR2) was up-regulated in OA patients and rat knee OA models, while celastrol inhibited TLR2 signal and its downstream nuclear factor-kappa B (NF-κB) phosphorylation. Conclusion: In summary, celastrol may improve OA by inhibiting the TLR2/NF-κB signaling pathway, which provides innovative strategies for the treatment of OA.

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PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway.

Publications

PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway.

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