7,960 results match your criteria inhibition mutated


Small molecule inhibition of deubiquitinating enzyme JOSD1 as a novel targeted therapy for leukemias with mutant JAK2.

Leukemia 2021 Jul 29. Epub 2021 Jul 29.

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Mutations in the Janus Kinase 2 (JAK2) gene resulting in constitutive kinase activation represent the most common genetic event in myeloproliferative neoplasms (MPN), a group of diseases involving overproduction of one or more kinds of blood cells, including red cells, white cells, and platelets. JAK2 kinase inhibitors, such as ruxolitinib, provide clinical benefit, but inhibition of wild-type (wt) JAK2 limits their clinical utility due to toxicity to normal cells, and small molecule inhibition of mutated JAK2 kinase activity can lead to drug resistance. Here, we present a strategy to target mutated JAK2 for degradation, using the cell's intracellular degradation machinery, while sparing non-mutated JAK2. Read More

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Flavan-3-ol Microbial Metabolites Modulate Proteolysis in Neuronal Cells Reducing Amyloid-beta (1-42) Levels.

Mol Nutr Food Res 2021 Jul 28:e2100380. Epub 2021 Jul 28.

School of Biosciences and Veterinary Medicine, University of Camerino, Italy.

Scope: Alzheimer's disease (AD) is a progressive neurodegeneration characterized by extensive protein aggregation and deposition in the brain, associated with defective proteasomal and autophagic-lysosomal proteolytic pathways. Since current drugs can only reduce specific symptoms, the identification of novel treatments is a major concern in AD research. Among natural compounds, (poly)phenols and their derivatives/metabolites are emerging as candidates in AD prevention due to their multiple beneficial effects. Read More

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Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis.

Nat Commun 2021 07 27;12(1):4559. Epub 2021 Jul 27.

San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (BRAF). All mice transplanted with BRAF-expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. Read More

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Characterization and functional study of a chimera galectin from yellow drum Nibea albiflora.

Int J Biol Macromol 2021 Jul 24. Epub 2021 Jul 24.

Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Fisheries College, Jimei University, Xiamen 361021, China. Electronic address:

Galectins are protein that participates in a variety of immune responses in the process of pathogenic infections. In the present study, a chimera galectin gene was screened from the transcriptome database of Nibea albiflora, which was named as YdGal-3. The results of qRT-PCR showed that the mRNA transcripts of YdGal-3 were ubiquitously distributed in all the detected tissues. Read More

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A Covalent Calmodulin Inhibitor as a Tool to Study Cellular Mechanisms of K-Ras-Driven Stemness.

Front Cell Dev Biol 2021 8;9:665673. Epub 2021 Jul 8.

Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.

Recently, the highly mutated oncoprotein K-Ras4B (hereafter K-Ras) was shown to drive cancer cell stemness in conjunction with calmodulin (CaM). We previously showed that the covalent CaM inhibitor ophiobolin A (OphA) can potently inhibit K-Ras stemness activity. However, OphA, a fungus-derived natural product, exhibits an unspecific, broad toxicity across all phyla. Read More

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Alternative strategies for optimizing treatment of chronic lymphocytic leukemia with complex clonal architecture.

Leuk Res 2021 Jul 6;110:106663. Epub 2021 Jul 6.

Back Bay Biosciences, Boston, MA, USA.

In silico simulation of pre-clinical and clinical data may accelerate pre-clinical and clinical trial advances, leading to benefits for therapeutic outcomes, toxicity and cost savings. Combining this with clonal architecture data may permit truly personalized therapy. Chronic lymphocytic leukemia (CLL) exhibits clonal diversity, evolution and selection, spontaneously and under treatment pressure. Read More

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Tumor response to EGFR/BRAF/MEK co-inhibition in a patient with EGFR mutated lung adenocarcinoma developing a BRAF mutation as an acquired resistance mechanism.

Lung Cancer 2021 Jul 21;159:42-44. Epub 2021 Jul 21.

Department of Pulmonology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 11, 1200 Brussels, Belgium; Université catholique de louvain, Institut de Recherche Expérimentale et Clinique (IREC)/Pôle de Pneumologie, Belgium. Electronic address:

EGFR-mutant adenocarcinomas represent 12% of unselected lung adenocarcinomas and 44% of never smoker adenocarcinomas in the Caucasian population. Activating mutations like exon19 deletion or exon21 Leu858Arg point mutations are predictive of tumor response to EGFR tyrosine kinase inhibitors. Unfortunately, acquired resistance inevitably occurs by the development of novel EGFR mutations, mutations in other genes, gene amplification, gene fusion or tumor transformation. Read More

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Generation and Characterization of a New Preclinical Mouse Model of EGFR-Driven Lung Cancer with MET-Induced Osimertinib Resistance.

Cancers (Basel) 2021 Jul 9;13(14). Epub 2021 Jul 9.

Oncogenic Pathways in Lung Cancer, Institut de Recherche en Cancérologie de Montpellier (IRCM)-Université de Montpellier (UM)-Institut Régional du Cancer de Montpellier (ICM), CEDEX 5, F-34298 Montpellier, France.

Despite the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to treat advanced lung cancer harboring EGFR-activating mutations, the prognosis remains unfavorable because of intrinsic and/or acquired resistance. We generated a new state-of-the-art mouse strain harboring the human EGFR oncogene and MET overexpression (EGFR/MET strain) that mimics the MET amplification occurring in one out of five patients with EGFR-mutated lung cancer that relapsed after treatment with osimertinib, a third-generation anti-EGFR TKI. We found that survival was reduced in EGFR/MET mice compared with mice harboring only EGFR (EGFR strain). Read More

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ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses.

J Exp Med 2021 Sep 23;218(9). Epub 2021 Jul 23.

Department of Cancer Immunology, Genentech, South San Francisco, CA.

Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. Read More

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September 2021

Inhalable nanocatchers for SARS-CoV-2 inhibition.

Proc Natl Acad Sci U S A 2021 07 2;118(29). Epub 2021 Jul 2.

Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China;

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Read More

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Tumor suppressor miR-193a-3p enhances efficacy of BRAF/MEK inhibitors in BRAF-mutated colorectal cancer.

Cancer Sci 2021 Jul 20. Epub 2021 Jul 20.

Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and epidermal growth factor receptor (EGFR) inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of BRAF inhibitor dabrafenib (DAB) and MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Read More

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Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma.

Clin Cancer Res 2021 Jul 20. Epub 2021 Jul 20.

Radiation Oncology, Dana-Farber Cancer Institute.

Pancreatic cancer is rapidly progressive and notoriously difficult to treat with cytotoxic chemotherapy and targeted agents. Recent demonstration of the efficacy of maintenance PARP inhibition in germline mutated pancreatic cancer has raised hopes that increased understanding of the DNA damage response pathway will lead to new therapies in both homologous recombination (HR) repair-deficient and proficient pancreatic cancer. Here, we review the potential mechanisms of exploiting HR deficiency, replicative stress, and DNA damage-mediated immune activation through targeted inhibition of DNA repair regulatory proteins. Read More

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Growth Suppression of Cancer Spheroids With Mutated KRAS by Low-toxicity Compounds from Natural Products.

Anticancer Res 2021 Aug;41(8):4061-4070

Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

Background/aim: Among compounds from natural products selectively suppressing the growth of cancer spheroids, which have mutant (mt) KRAS, NP910 was selected and its derivatives explored.

Materials And Methods: The area of HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in three-dimensional floating (3DF) cultures treated with 18 NP910 derivatives. The 50% cell growth inhibition (GI50) was determined by long-term 3DF (LT3DF) culture and nude mice assay. Read More

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MTA2 sensitizes gastric cancer cells to PARP inhibition by induction of DNA replication stress.

Transl Oncol 2021 Jul 17;14(10):101167. Epub 2021 Jul 17.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address:

Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib selectively kills cancer cells with BRCA-deficiency and is approved for BRCA-mutated breast, ovarian and pancreatic cancers by FDA. However, phase III study of olaparib failed to show a significant improvement in overall survival in patients with gastric cancer (GC). To discover an effective biomarker for GC patient-selection in olaparib treatment, we analyzed proteomic profiling of 12 GC cell lines. Read More

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BioID-screening identifies PEAK1 and SHP2 as components of the Alk "proximitome" in neuroblastoma cells.

J Mol Biol 2021 Jul 14:167158. Epub 2021 Jul 14.

Department of Medical Biochemistry and Cell Biology, Instititute of Biomedicine. Electronic address:

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is mutated in approximately 10% of pediatric neuroblastoma (NB). To shed light on ALK-driven signaling processes, we employed BioID-based in vivo proximity labeling to identify molecules that interact intracellularly with ALK. NB-derived SK-N-AS and SK-N-BE(2) cells expressing inducible ALK-BirA* fusion proteins were generated and stimulated with ALKAL ligands in the presence and absence of the ALK tyrosine kinase inhibitor (TKI) lorlatinib. Read More

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Inhibition of HSP90 S-nitrosylation Alleviates Cardiac Fibrosis via TGFβ/SMAD3 Signaling Pathway.

Br J Pharmacol 2021 Jul 15. Epub 2021 Jul 15.

Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.

Background And Purpose: Effective anti-fibrotic therapeutic solutions are unavailable so far. The heat shock protein 90 (HSP90) exerts deleterious effects in some fibrotic diseases. S-nitrosylation (SNO) of HSP90 affects its own function, however, little is known about its role in pathological stress. Read More

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Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration.

Cell Rep 2021 Jul;36(2):109363

Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ∼10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage. Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Read More

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Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells.

Nat Commun 2021 07 13;12(1):4288. Epub 2021 Jul 13.

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. Read More

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MicroRNA-324-5p-CUEDC2 Axis Mediates Gain-of-Function Mutant p53-Driven Cancer Stemness.

Mol Cancer Res 2021 Jul 13. Epub 2021 Jul 13.

ICMR Emeritus Scientist, CSIR-Indian Institute of Chemical Biology

Regulation of cancer stemness has recently emerged as a new gain-of-function (GOF) property of mutant p53. In this study, we identify miR-324-5p as a critical epigenetic regulator of cancer stemness and demonstrate its role in mediating GOF-mutant p53-driven stemness phenotypes. We report that miR-324-5p is upregulated in human cancer cell lines and non-small cell lung carcinoma (NSCLC) tumors carrying TP53 gain-of-function mutations. Read More

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Telomere dysfunction instigates inflammation in inflammatory bowel disease.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Read More

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Comprehensive immunomolecular profiling of endometrial carcinoma: A tertiary retrospective study.

Gynecol Oncol 2021 Jul 9. Epub 2021 Jul 9.

Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.

Objective: Combined immunohistochemical and molecular classification using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) independently predicts prognosis in endometrial carcinoma (EC). As next-generation sequencing (NGS) is entering clinical practice, we evaluated whether more comprehensive immunomolecular profiling (CIMP), including NGS and extended immunohistochemical analysis, could further refine the current ProMisE classification.

Methods: A series of 120 consecutive ECs, classified according to ProMisE, was stained immunohistochemically for CD3, CD8, PD-L1, beta-catenin and L1CAM. Read More

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A tipping-point for apoptosis following dual inhibition of HER2 signaling network by T-DM1 plus GDC-0980 maximizes anti-tumor efficacy.

Am J Cancer Res 2021 15;11(6):2867-2892. Epub 2021 Jun 15.

Translational Oncology Laboratory, Avera Cancer Institute Sioux Falls, SD, USA.

HER2 signaling network and its complex relationship with the PI3K-AKT-mTOR pathway explain the acquired resistance to anti-HER2 therapy observed in clinics. Such complexity has been clinically evident from the limited efficacy of data in the BOLERO-1 and BOLERO-3 trials, which tested combinations of trastuzumab (T), everolimus, and chemotherapy in women with HER2+ advanced BC. In the following MARIANNE trial also, a combination of T-DM1 plus pertuzumab delivered a non-inferior but yet not superior PFS compared to trastuzumab plus a taxane. Read More

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Targeting Bruton's Tyrosine Kinase in CLL.

Front Immunol 2021 23;12:687458. Epub 2021 Jun 23.

Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States.

Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Covalent BTK inhibitors (BTKis) led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups with aberration and unmutated immunoglobulin heavy-chain variable-region gene (IGHV). Ibrutinib and acalabrutinib are approved by the US Food and Drug Administration for the treatment of CLL and other B-cell lymphomas, and zanubrutinib, for patients with mantle cell lymphoma. Read More

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Type II c-Met inhibitors: molecular insight into crucial interactions for effective inhibition.

Mol Divers 2021 Jul 11. Epub 2021 Jul 11.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

The c-Met tyrosine kinase plays an important role in human cancers. Preclinical studies demonstrated that c-Met is over-expressed, mutated and amplified in a variety of human tumor types and design of more potent c-Met inhibitors is a priority. In this study, 14 molecular dynamics simulations of potent type II c-Met inhibitors were run to resolve the critical interactions responsible for high affinity of ligands towards c-Met considering the essential flexibility of protein-ligand interactions. Read More

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The Chk2-PKM2 axis promotes metabolic control of vasculogenic mimicry formation in p53-mutated triple-negative breast cancer.

Oncogene 2021 Jul 9. Epub 2021 Jul 9.

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Vasculogenic mimicry (VM) formation, which participates in the process of neovascularization, is highly activated in p53-mutated triple-negative breast cancer (TNBC). Here, we show that Chk2 is negatively correlated with VM formation in p53-mutated TNBC. Its activation by DNA-damaging agents such as cisplatin, etoposide, and DPT reduces VM formation. Read More

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Suppression of DNA Polymerase β Activity Is Synthetically Lethal in BRCA1-Deficient Cells.

ACS Chem Biol 2021 Jul 9. Epub 2021 Jul 9.

Department of Chemistry, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, United States.

People whose cells express mutated forms of the BRCA1 tumor suppressor are at a higher risk for developing cancer. BRCA1-deficient cells are defective in DNA double-strand break repair. The inhibition of poly(ADP-ribose) polymerase 1 in such cells is a synthetically lethal, cytotoxic effect that has been exploited to produce anticancer drugs such as Olaparib. Read More

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A mutual information-based in vivo monitoring of adaptive response to targeted therapies in melanoma.

Neoplasia 2021 Aug 5;23(8):775-782. Epub 2021 Jul 5.

Dermato-Oncology Unit, Division of Dermatology, University Hospital of Geneva, Switzerland; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland. Electronic address:

The mechanisms of adaptive resistance to genetic-based targeted therapies of solid malignancies have been the subject of intense research. These studies hold great promise for finding co-targetable hub/pathways which in turn would control the downstream non-genetic mechanisms of adaptive resistance. Many such mechanisms have been described in the paradigmatic BRAF-mutated melanoma model of adaptive response to BRAF inhibition. Read More

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The associations between THBD c.1418C>T polymorphism and lower extremity deep vein thrombosis or endothelial progenitor cell.

Int Angiol 2021 Jul 8. Epub 2021 Jul 8.

Department of General Surgery, the First People's Hospital of Yunnan Province, Kunming, Yunnan, China -

Background: Studies have shown that the thrombomodulin gene (THBD) c.1418C>T polymorphism is associated with a variety of cardiovascular diseases. However, the study of THBD c. Read More

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Still a burning question: the interplay between inflammation and fibrosis in myeloproliferative neoplasms.

Curr Opin Hematol 2021 Jul 15. Epub 2021 Jul 15.

Department of Developmental Biology Oncode Institute, Erasmus MC, Rotterdam, The Netherlands Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University, Aachen, Germany.

Purpose Of Review: Bone marrow fibrosis is the progressive replacement of blood-forming cells by reticulin fibres, caused by the acquisition of somatic mutations in hematopoietic stem cells. The molecular and cellular mechanisms that drive the progression of bone marrow fibrosis remain unknown, yet chronic inflammation appears to be a conserved feature in most patients suffering from myeloproliferative neoplasms.

Recent Findings: Here, we review recent literature pertaining to the role of inflammation in driving bone marrow fibrosis, and its effect on the various hematopoietic and nonhematopoietic cell populations. Read More

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