The effect of methylation on the let-7-BCL2L1-BCL2 axis and the potential use of hypomethylating and BH3 mimetic drugs in histiocytic neoplasms
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PROVIDER: PRJNA1170180 | ENA |
REPOSITORIES: ENA
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Project description:The histiocytoses [Erdheim-Chester Disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman-Destombes disease (RDD)] are characterized by the infiltration of monocytes, macrophages, and dendritic cells in normal tissues, leading to significant morbidity due to disruption of critical organ systems. While their pathogenesis involves MAPK-ERK pathway mutations, their epigenetic landscape remains poorly understood. Epigenetic mechanisms such as DNA methylation, histone modification, and non-coding RNA are crucial in gene expression regulation and cancer development. We previously identified a distinct non-coding RNA profile in histiocytosis patients compared to controls. We analyzed the DNA methylation profile of 30 patients and found significant alterations in 23,322 methylation sites compared to controls, independent of age, gender, mutation type, or disease site. We observed a significant hypermethylation in the let-7b transcript, resulting in decreased let-7b expression. This led to the lack of regulation on the anti-apoptotic proteins BCL2L1, which was overexpressed in 21/21 (100%) patients' biopsies and BCL2 in 11/21 biopsies (52%). Treatment with the hypomethylating agent, 5-Azacytidine, restored let-7b expression, reduced BCL2L1 levels, and induced apoptosis in BRAFV600E mutant cells. Additionally, BCL2L1 and BCL2 inhibitors also induced apoptosis. This novel epigenetic mechanism suggests that hypomethylating agents or BH3 mimetic drugs may offer new therapeutic targets for histiocytosis.
2024-11-14 | GSE279030 | GEO
Project description:TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed TP53-mutant mouse B lymphoma, human NK/T lymphoma and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
2024-04-25 | GSE261373 | GEO
Project description:BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL1 are in clinical trials. Yet, drug resistance eventually ensues, highlighting the urgency to understand the underlying mechanisms. Our genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy regulators sensitizes AML to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), a GTPase that controls mitochondrial dynamics and the degradation of damaged mitochondria through mitophagy. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. MFN2 inactivation, using a novel small molecule inhibitor, and pharmacologic inhibition of mitophagy synergizes with BH3 mimetics. Overall, targeting of mitophagy along with BCL2-family members is a promising strategy to overcome drug resistance in AML.
2023-07-10 | GSE182401 | GEO
Project description:Brevundimonas sp. BH3 Genome sequencing
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Project description:Molecular Genetics of Histiocytic Sarcomas
| PRJNA507682 | ENA
Project description:Molecular Genetics of Histiocytic Sarcomas
| PRJNA507681 | ENA
Project description:Background: The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors has value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Methods: Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. Results: QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. Conclusions: This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Extraploration of this downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human. Microarray expression dataset including STHS: Soft Tissue (localized) Histiocytic Sarcoma; VHS: Visceral (disseminated)Histiocytic Sarcoma; together with normal spleen (NS) samples. Comparisons were analysed in dyeswap on a 2-color platform against a common reference sample, consisting of a multitude of canine organs, including liver, spleen, kidney, lung, hart, intestine and bone.
2013-08-07 | E-GEOD-45832 | biostudies-arrayexpress
Project description:Ochrobactrum sp. BH3 Genome sequencing and assembly
| PRJNA501396 | ENA
Project description:Background: The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors has value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Methods: Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. Results: QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. Conclusions: This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Extraploration of this downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human.
2013-08-07 | GSE45832 | GEO