Hematopoietic stem cell aging and leukemia transformation

Blood, Journal Year: 2023, Volume and Issue: 142(6), P. 533 - 542

Published: Feb. 17, 2023

With aging, hematopoietic stem cells (HSCs) have an impaired ability to regenerate, differentiate, and produce entire repertoire of mature blood immune cells. Owing dysfunctional hematopoiesis, the incidence hematologic malignancies increases among elderly individuals. Here, we provide update on HSC-intrinsic -extrinsic factors processes that were recently discovered contribute functional decline HSCs during aging. In addition, discuss targets timing intervention approaches maintain HSC function aging extent which these same may prevent or delay transformation malignancies.

Language: Английский

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Ageing-related bone and immunity changes: insights into the complex interplay between the skeleton and the immune system

Bone Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Aug. 5, 2024

Abstract Ageing as a natural irreversible process inherently results in the functional deterioration of numerous organ systems and tissues, including skeletal immune systems. Recent studies have elucidated intricate bidirectional interactions between these two In this review, we provide comprehensive synthesis molecular mechanisms cell ageing. We further discuss how age-related changes influence system consequent impact alterations on system. Finally, highlight clinical implications findings propose potential strategies to promote healthy ageing reduce pathologic both

Language: Английский

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Bone marrow inflammation in haematological malignancies

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: 24(8), P. 543 - 558

Published: March 15, 2024

Language: Английский

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A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML

Blood Cancer Discovery, Journal Year: 2023, Volume and Issue: 4(5), P. 394 - 417

Published: July 19, 2023

Abstract Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, adapted single-cell RNA sequencing, we decipher the predicted signaling tissue-resident hematopoietic stem/progenitor (HSPC) neoplastic counterparts with native niches in human bone marrow. LEPR+ stromal are identified as central regulators of hematopoiesis through interactions all Inflammatory niche remodeling resulting deprivation critical HSPC regulatory factors to repress high-output stem cell subsets NPM1-mutated acute myeloid leukemia (AML), relative resistance clonal cells. Stromal gene signatures reflective associated reduced relapse rates favorable outcomes after chemotherapy across genetic risk categories. Elucidation intercellular defining AML, thus, predicts that inflammatory drives tissue repression selection but may pose a vulnerability for relapse-initiating context chemotherapeutic treatment. Significance: Tumor-promoting inflammation considered enabling characteristic tumorigenesis, mechanisms remain incompletely understood. By deciphering environment, identify determinant normal clinical AML. See related commentary Lisi-Vega Méndez-Ferrer, p. 349. This article featured Selected Articles from Issue, 337

Language: Английский

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Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats

Biology of Sex Differences, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 13, 2024

Abstract Background Major depressive disorder (MDD) is a recurring affective that two times more prevalent in females than males. Evidence supports immune system dysfunction as major contributing factor to MDD, notably sexually dimorphic manner. Nuclear erythroid 2-related 2 (Nrf2), regulator of antioxidant signalling during inflammation, dysregulated many chronic inflammatory disorders; however, its role depression and the associated sex differences have yet be explored. Here, we investigated sex-specific antidepressant cognitive effects potent Nrf2 activator dimethyl fumarate (DMF), well gene expression profiles. Methods Male female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected 8 weeks unpredictable stress. The effect treatment on stress-induced depression- anxiety-like behaviours, deficits recognition spatial learning memory then assessed. Sex hippocampal (HIP) responses also evaluated. Results stress exposure had male but not rats, no anxiolytic either sex. Recognition impaired chronically stressed males females, respectively, rescued these deficits. Further, elicited alterations HIP expression, which normalized animals DMF. Of note, most differentially expressed genes by related antioxidant, responses. Conclusions Collectively, findings may support greater processes rodent model depression. This suggests pharmacotherapies target potential an effective for

Language: Английский

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Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1–Mediated Mitochondrial Fusion

Molecular Cancer Research, Journal Year: 2023, Volume and Issue: 21(12), P. 1366 - 1378

Published: Sept. 12, 2023

Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary secondary drug resistance. Elevated serum IL6 levels have been observed in patients with AML are associated chemoresistance. Chemoresistant cells highly dependent on oxidative phosphorylation (OXPHOS), mitochondrial network remodeling is essential for function. However, IL6-mediated regulation its effectiveness as therapeutic target remain unclear. We aimed to determine the mechanisms through which facilitates development chemoresistance cells. upregulated mitofusin 1 (MFN1)-mediated fusion, promoted OXPHOS, induced MFN1 knockdown impaired effects function In MLL::AF9 fusion gene-induced mouse model, reduced chemosensitivity cytarabine (Ara-C), commonly used antileukemia drug, accompanied by increased expression, OXPHOS status. contrast, anti-IL6 antibodies downregulated suppressed enhanced curative Ara-C, prolonged overall survival. conclusion, MFN1-mediated AML, facilitated respiration, turn, inducing Thus, targeting may implications overcoming AML.IL6 treatment induces promotes confers Targeting mitochondria promising strategy enhance AML.

Language: Английский

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Chronic inflammation can transform the fate of normal and mutant hematopoietic stem cells

Experimental Hematology, Journal Year: 2023, Volume and Issue: 127, P. 8 - 13

Published: Aug. 28, 2023

Language: Английский

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Mesenchymal Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 30, 2024

Abstract Clonal hematopoiesis (CH) can predispose to blood cancers due enhanced fitness of mutant hematopoietic stem and progenitor cells (HSPCs), but the mechanisms driving this progression are not understood. We hypothesized that malignant is related microenvironment-remodelling properties CH-mutant HSPCs. Single-cell transcriptomic profiling bone marrow microenvironment in Dnmt3a R878H/+ mice revealed signatures cellular senescence mesenchymal stromal (MSCs). HSPCs caused MSCs upregulate markers SA-β-gal, BCL-2, BCL-xL, Cdkn1a (p21) Cdkn2a (p16), ex vivo . This effect was cell contact-independent be replicated by IL-6 or TNFα, which produced Depletion senescent reduced CH myeloid neoplasms using a sequentially inducible ; Npm1 -mutant model. Thus, reprogram their via induction, creating self-reinforcing niche favoring progression. Statement Significance Mesenchymal induced drives clonal initiation hematologic malignancy.

Language: Английский

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Systemic inflammatory autoimmune disease before allogeneic hematopoietic stem cell transplantation is a risk factor for death in patients with myelodysplastic syndrome or chronic myelomonocytic leukemia

Annals of Hematology, Journal Year: 2024, Volume and Issue: 103(6), P. 2059 - 2072

Published: April 25, 2024

Language: Английский

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Recent trends in research on the role of cholesterol in leukemia: a bibliometric and visualization study

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 23, 2025

Background Cholesterol metabolism significantly impacts leukemia pathophysiology, affecting tumor cell survival, proliferation, and treatment resistance. This study employs bibliometric analysis visualization techniques to investigate research trends regarding cholesterol in identify key hotspots. Methods A systematic search of the Web Science Core Collection was performed for literature published from 1980 2024 using keywords “cholesterol” “leukemia,” yielding 1,220 articles. Bibliometric tools like VOSviewer CiteSpace were utilized visualizing citation networks thematic clusters. Results The comprised publications produced by 6,771 researchers across 1,756 institutions 68 countries, 576 journals with 5,903 unique keywords. Publication output demonstrated a significant rise 2024, peaking 2022. United States led total (381) citations (40,462), followed China (137 articles) Japan (102). Notably, U.S. had lower average than those Germany Brazil. Key included University São Paulo, Medical College Wisconsin, National Cancer Institute, prominent authors such as Maranhao Raul C. Girotti Albert W. journal Research most prolific, while Blood highest frequency. Major areas encompassed molecular biology, immunology, medicine, focusing on cholesterol-leukemia link. Keyword co-occurrence co-citation analyses reveal increasing interest topics STAT3, multidrug resistance, interactions. These insights suggest crucial further research. Discussion Our findings emphasize cholesterol’s significance leukemia, indicating its potential therapeutic target. Further exploration at intersection requires multidisciplinary collaboration. Conclusion delineates evolving landscape role pinpointing emerging future directions inform effective strategies.

Language: Английский

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