Targeting cholesterol homeostasis in hematopoietic malignancies

Brendolan, Andrea; Russo, Vincenzo

doi:10.1182/blood.2021012788

Cited by 20 publications

(20 citation statements)

References 103 publications

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“…In this study, we expanded the notion of co‐existing functional subsets of Mo within TME of DLBCL, revealing striking association of the LXRα transcript (encoded by NR1H3 gene) expression with the M1 phenotype of Mo with putative anti‐tumor effect. Accumulating data highlighted the relevance of LXRs in anti‐cancer immune surveillance and described mechanisms of LXR axis activity in diverse immune cytotypes 32,33 . Particularly, the function of LXRα remains controversial as it can regulate a broad range of activities in specific subsets of accessory cells, such as Mo, in the context of various human cancers 34 .…”

Section: Discussionmentioning

confidence: 99%

NR1H3 (LXRα) is associated with pro‐inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b‐cell lymphoma

Vegliante

Mazzara

Zaccaria

et al. 2022

Hematological Oncology

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The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like proinflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3 high patients displayed longer survival compared with NR1H3 low cases and a highresolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo-related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

NR1H3 (LXRα) is associated with pro‐inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b‐cell lymphoma

Vegliante

Mazzara

Zaccaria

et al. 2022

Hematological Oncology

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“…Pathway enrichment analysis with these 235 genes determined IL-2/ STAT5 signaling pathway was the most highly enriched. In addition, it was reported that other enriched pathways including mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, androgen response, cholesterol homeostasis, estrogen response, and interferon gamma response were related to AML (44)(45)(46)(47)(48). Prognostic models based on these gene pathways might be alternative candidates for predicting prognosis of AML patients.…”

Section: Discussionmentioning

confidence: 99%

A Prognostic Model for Acute Myeloid Leukemia Based on IL-2/STAT5 Pathway-Related Genes

et al. 2022

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Accurate prognostic stratification of patients can provide guidance for personalized therapy. Many prognostic models for acute myeloid leukemia (AML) have been reported, but most have considerable inaccuracies due to contained variables with insufficient capacity of predicting survival and lack of adequate verification. Here, 235 genes strongly related to survival in AML were systematically identified through univariate Cox regression analysis of eight independent AML datasets. Pathway enrichment analysis of these 235 genes revealed that the IL-2/STAT5 signaling pathway was the most highly enriched. Through Cox proportional-hazards regression model and stepwise algorithm, we constructed a six-gene STAT5-associated signature based on the most robustly survival-related genes related to the IL-2/STAT5 signaling pathway. Good prognostic performance was observed in the training cohort (GSE37642-GPL96), and the signature was validated in seven other validation cohorts. As an independent prognostic factor, the STAT5-associated signature was positively correlated with patient age and ELN2017 risk levels. An integrated score based on these three prognostic factors had higher prognostic accuracy than the ELN2017 risk category. Characterization of immune cell infiltration indicated that impaired B-cell adaptive immunity, immunosuppressive effects, serious infection, and weakened anti-inflammatory function tended to accompany high-risk patients. Analysis of in-house clinical samples revealed that the STAT5-assocaited signature risk scores of AML patients were significantly higher than those of healthy people. Five chemotherapeutic drugs that were effective in these high-risk patients were screened in silico. Among the five drugs, MS.275, a known HDAC inhibitor, selectively suppressed the proliferation of cancer cells with high STAT5 phosphorylation levels in vitro. Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments.

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“…In conditions of high cholesterol levels, INSIG, SCAP and SREBP2 form a stable trimolecular complex in the ER, thereby blocking the export and activation of SREBP2 and finally blocking the de novo cholesterol synthetic route. Moreover, excess oxysterols or desmosterol bind and activate the LXR/RXR heterodimer, which in turn activates specific LXR target genes, such as ATP-binding cassette transporters A1 and G1 (ABCA1 and ASCG1), allowing excess cholesterol to be transported to the liver and excreted as bile acids ( Figure 1 ) ( 78 ).…”

Section: Cholesterol Metabolism In Hematological Malignanciesmentioning

confidence: 99%

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy

Zhang

Chang²,

Liu³

et al. 2022

Front. Oncol.

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Hematological malignancies are one of the most lethal illnesses that seriously threaten human life and health. Lipids are important constituents of various biological membranes and substances for energy storage and cell signaling. Furthermore, lipids are critical in the normal physiological activities of cells. In the process of the lethal transformation of hematological malignancies, lipid metabolism reprogramming meets the material and energy requirements of rapidly proliferating and dividing tumor cells. A large number of studies have shown that dysregulated lipid metabolism, commonly occurs in hematological malignancies, mediating the proliferation, growth, migration, invasion, apoptosis, drug resistance and immune escape of tumor cells. Targeting the lipid metabolism pathway of hematological malignancies has become an effective therapeutic approach. This article reviews the oncogenic mechanisms of lipid metabolism reprogramming in hematological malignancies, including fatty acid, cholesterol and phospholipid metabolism, thereby offering an insight into targeting lipid metabolism in the treatment of hematological malignancies.

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Targeting cholesterol homeostasis in hematopoietic malignancies

Cited by 20 publications

References 103 publications

NR1H3 (LXRα) is associated with pro‐inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b‐cell lymphoma

NR1H3 (LXRα) is associated with pro‐inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b‐cell lymphoma

A Prognostic Model for Acute Myeloid Leukemia Based on IL-2/STAT5 Pathway-Related Genes

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy

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