SMARCD1 negatively regulates myeloid differentiation of leukemic cells via epigenetic mechanisms

Saha, Subha; Samal, Priyanka; Madhulika, Swati; Murmu, Krushna Chandra; Chakraborty, Sohini; Basu, Jhinuk; Barik, Subhabrata; Jena, Kautilya Kumar; Das, Asima; Chauhan, Santosh; Prasad, Punit

doi:10.1182/bloodadvances.2021006235

Cited by 4 publications

(4 citation statements)

References 12 publications

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“…SMARCD1 functions within the chromatin-remodeling BAF complex and has been described as a key mediator of cardiac and myeloid development 21,22 . Thus, we next asked if altered Smarcd1 expression could modify gene expression programs by changing the regions of open chromatin, and whether any patterns may be common to both Smarcd1 KD and Smarcd1 OE cells.…”

Section: Resultsmentioning

confidence: 99%

SMARCD1 is a “Goldilocks” metastasis modifier

Ross,

Gong,

Jenkins

et al. 2024

Preprint

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Breast cancer is the most frequently diagnosed cancer worldwide, constituting around 15% of all diagnosed cancers in 2023. The predominant cause of breast cancer-related mortality is metastasis to distant essential organs, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. However, through our use of meiotic genetics to study inherited transcriptional network regulation, we have identified a new class of Goldilocks genes that are promising candidates for the development of metastasis-targeted therapeutics. Building upon previous work that implicated the CCR4-NOT RNA deadenylase complex in metastasis, we now demonstrate that the RNA-binding proteins (RNA-BPs) NANOS1, PUM2, and CPSF4 also regulate metastatic potential. Using cell lines, 3D culture, mouse models, and clinical data, we pinpoint Smarcd1 mRNA as a key target of all three RNA-BPs. Strikingly, both high and low expression of Smarcd1 is associated with positive clinical outcomes, while intermediate expression significantly reduces the probability of survival. Applying the theory of essential genes from evolution, we identify an additional 50 genes that span several cellular processes and must be maintained within a discrete window of expression for metastasis to occur. In the case of Smarcd1, small perturbations in its expression level significantly reduce metastasis in laboratory mouse models and alter splicing programs relevant to the ER+/HER2-enriched breast cancer subtype. The identification of subtype-specific Goldilocks metastasis modifier genes introduces a new class of genes and potential catalogue of novel targets that, when therapeutically nudged in either direction, may significantly improve late-stage patient outcomes.

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Section: Resultsmentioning

confidence: 99%

SMARCD1 is a “Goldilocks” metastasis modifier

Ross,

Gong,

Jenkins

et al. 2024

Preprint

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“…Among the top 5 genes differentiating the 2 cell subtypes, TREM2 , a member of the Triggering Receptor Expressed on Myeloid cells (TREM) family, was more than 8-fold upregulated in M2-like macrophages compared to M1-like macrophages, and was largely not expressed by monocytes (<1 TPM; Supplementary Table 2 ). Conversely, SMARCD3 , a gene specifically enriched in monocytes 31 , was one of the top 5 genes of the quanTIseq monocyte signature and was poorly expressed by M2-like macrophages (Supplementary Table 3 ). TREM2 expression was associated with a shorter PFS, although not reaching statistical significance, and with a significantly shorter OS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma

Le Saux,

Ardin,

Berthet

et al. 2024

Nat Commun

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PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8+PD-1+ T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2+ endothelial cells, could overcome immune resistance of ovarian cancers.

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“…The HL60 model system has been used very effectively to study the effects of drugs and small molecules that can induce either differentiation and/or apoptosis ( Huang et al, 2019 ). The functional role of genes of interest was also studied using RNAi strategies to understand their role in myeloid differentiation ( Saha et al, 2022 ). In this regard, to validate the effectiveness of HL60 as an important leukemic cell line model, we compared the transcriptome of the uninduced HL60 cells and the primary leukemic blasts and obtained 68.03% of genes with a similar expression profile, which indicated a fair correlation between the uninduced HL60 cells and the leukemic blasts.…”

Section: Discussionmentioning

confidence: 99%

Molecular and epigenetic alterations in normal and malignant myelopoiesis in human leukemia 60 (HL60) promyelocytic cell line model

Basu

Madhulika²,

Murmu³

et al. 2023

Front. Cell Dev. Biol.

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In vitro cell line model systems are essential in supporting the research community due to their low cost, uniform culturing conditions, homogeneous biological resources, and easy experimental design to study the cause and effect of a gene or a molecule. Human leukemia 60 (HL60) is an in-vitro hematopoietic model system that has been used for decades to study normal myeloid differentiation and leukemia biology. Here, we show that IMDM supplemented with 20% FBS is an optimal culturing condition and induces effective myeloid differentiation compared with RPMI supplemented with 10% FBS when HL60 is induced with 1α,25-dihydroxyvitamin D3 (Vit D3) and all-trans retinoic acid (ATRA). The chromatin organization is compacted, and the repressive epigenetic mark H3K27me3 is enhanced upon HL60-mediated terminal differentiation. Differential gene expression analysis obtained from RNA sequencing in HL60 cells during myeloid differentiation showed the induction of pathways involved in epigenetic regulation, myeloid differentiation, and immune regulation. Using high-throughput transcriptomic data (GSE74246), we show the similarities (genes that did not satisfy |log2FC|>1 and FDR<0.05) and differences (FDR <0.05 and |log2FC|>1) between granulocyte-monocyte progenitor vs HL60 cells, Vit D3 induced monocytes (vMono) in HL60 cells vs primary monocytes (pMono), and HL60 cells vs leukemic blasts at the transcriptomic level. We found striking similarities in biological pathways between these comparisons, suggesting that the HL60 model system can be effectively used for studying myeloid differentiation and leukemic aberrations. The differences obtained could be attributed to the fact that the cellular programs of the leukemic cell line and primary cells are different. We validated several gene expression patterns for different comparisons with CD34+ cells derived from cord blood for myeloid differentiation and AML patients. In addition to the current knowledge, our study further reveals the significance of using HL60 cells as in vitro model system under optimal conditions to understand its potential as normal myeloid differentiation model as well as leukemic model at the molecular level.

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SMARCD1 negatively regulates myeloid differentiation of leukemic cells via epigenetic mechanisms

Cited by 4 publications

References 12 publications

SMARCD1 is a “Goldilocks” metastasis modifier

SMARCD1 is a “Goldilocks” metastasis modifier

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma

Molecular and epigenetic alterations in normal and malignant myelopoiesis in human leukemia 60 (HL60) promyelocytic cell line model

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