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Hematology (Amsterdam, Netherlands) Dec 2024Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers... (Review)
Review
BACKGROUND
Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients' clinical manifestations and outcomes.
METHODS
A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021.
RESULTS
A total of 50 patients with -positive MPN were reviewed with a median follow-up of three years (1-11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with type 1, 21 (42%) patients with type 2, and 5 (10%) patients with none Type 1, none Type 2 mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 and mutations, and 1(2%) with type 1 and mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying 1 mutations, and 1 (2%) patient progressed to AML with 2 mutation.
CONCLUSION
The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.
Topics: Humans; Calreticulin; Mutation; Male; Female; Myeloproliferative Disorders; Tertiary Care Centers; Middle Aged; Adult; Retrospective Studies; Qatar; Aged
PubMed: 38804886
DOI: 10.1080/16078454.2024.2360246 -
Scientific Reports May 2024Telocytes are a unique interstitial cell type that functions in adulthood and embryogenesis. They have characteristic immunohistochemical phenotypes while acquiring...
Telocytes are a unique interstitial cell type that functions in adulthood and embryogenesis. They have characteristic immunohistochemical phenotypes while acquiring different immunohistochemical properties related to the organ microenvironment. The present study aims to investigate the immunohistochemical features of embryonic telocytes during myogenesis and describe their morphology using light microscopy and TEM. Telocytes represent a major cellular constituent in the interstitial elements. They had distinguished telopodes and podoms and formed a 3D interstitial network in the developing muscles. They formed heterocellular contact with myoblasts and nascent myotubes. Telocytes also had distinctive secretory activity. Telocytes identified by CD34. They also express CD68 and MMP-9 to facilitate the development of new tissues. Expression of CD21 by telocytes may reveal their function in immune defense. They also express VEGF, which regulates angiogenesis. In conclusion, the distribution and immunological properties of telocytes in the myogenic tissue indicate that telocytes provide biological and structural support in the development of the myogenic tissue architecture and organization.
Topics: Telocytes; Animals; Muscle Development; Immunohistochemistry; Mice; Antigens, CD; Antigens, CD34; Cellular Microenvironment; Matrix Metalloproteinase 9; Antigens, Differentiation, Myelomonocytic; Vascular Endothelial Growth Factor A; Myoblasts
PubMed: 38802438
DOI: 10.1038/s41598-024-62103-1 -
Frontiers in Immunology 2024levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. can be produced by Th17 cells and locally within joints by tissue-resident...
OBJECTIVES
levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. can be produced by Th17 cells and locally within joints by tissue-resident cells. induces osteoblast mineralization . As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of in spondyloarthritis.
METHODS
Serum, peripheral blood mononuclear cells ( = 15-35) and synovial tissue ( = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR.
RESULTS
Synovial tissue of axSpA patients shows significantly more -positive cells than that of HCs ( < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs ( < 0.001 and < 0.01). However, peripheral blood CD4 T cells from axSpA and PsA patients show higher positivity for in the PrimeFlow assay compared with HCs. CD4 memory T cells from axSpA patients produce more under Th17-favoring conditions (IL-1β and IL-23) than cells from PsA and RA patients or HCs.
CONCLUSION
production is increased in the synovial tissue of SpA and can be localized to CD68 macrophage-like synoviocytes, whereas circulating Th17 cells are only modestly enriched. Considering the osteoproliferative properties of , this offers new therapeutic options independent of Th17 pathways.
Topics: Humans; Arthritis, Psoriatic; Synoviocytes; Male; Adult; Female; Antigens, CD; Interleukins; Middle Aged; Antigens, Differentiation, Myelomonocytic; Axial Spondyloarthritis; Th17 Cells; Synovial Membrane; Joints; Arthritis, Rheumatoid
PubMed: 38799447
DOI: 10.3389/fimmu.2024.1355824 -
Frontiers in Immunology 2024Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and...
BACKGROUND
Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. Our previous results suggest that SHP2 plays a crucial role in reprogramming the phenotype of TAMs. Thus, we hypothesized that SHP2 TAM may predict the treatment efficacy of non-small cell lung cancer NSCLC patients as a biomarker.
METHODS
We analyzed cancer tissue samples from 79 NSCLC patients using multiplex fluorescence (mIF) staining to visualize various SHP-2 TAM subpopulations (CD68SHP2, CD68CD86, CD68 + 206, CD68 CD86SHP2, CD68 CD206SHP2) and T cells (CD8 Granzyme B ) of immune cells. The immune cells proportions were quantified in the tumor regions (Tumor) and stromal regions (Stroma), as well as in the overall tumor microenvironment (Tumor and Stroma, TME). The analysis endpoint was overall survival (OS), correlating them with levels of cell infiltration or effective density. Cox regression was used to evaluate the associations between immune cell subsets infiltration and OS. Correlations between different immune cell subsets were examined by Spearman's tests.
RESULTS
In NSCLC, the distribution of different macrophage subsets within the TME, tumor regions, and stroma regions exhibited inconsistency. The proportions of CD68 SHP2 TAMs (P < 0.05) were higher in tumor than in stroma. And the high infiltration of CD68SHP2 TAMs in tumor areas correlated with poor OS (P < 0.05). We found that the expression level of SHP2 was higher in M2-like macrophages than in M1-like macrophages. The CD68SHP2 subset proportion was positively correlated with the CD68CD206 subset within TME (P < 0.0001), tumor (P < 0.0001) and stroma (P < 0.0001).
CONCLUSIONS
The high infiltration of CD68SHP2 TAMs predict poor OS in NSCLC. Targeting SHP2 is a potentially effective strategy to inhibit M2-phenotype polarization. And it provides a new thought for SHP2 targeted cancer immunotherapy.
Topics: Humans; Tumor Microenvironment; Carcinoma, Non-Small-Cell Lung; Female; Lung Neoplasms; Antigens, CD; Male; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Antigens, Differentiation, Myelomonocytic; Middle Aged; Tumor-Associated Macrophages; Aged; Biomarkers, Tumor; Macrophages; Prognosis; Adult; CD68 Molecule
PubMed: 38799432
DOI: 10.3389/fimmu.2024.1396719 -
BioRxiv : the Preprint Server For... Jun 2024PTPN11 encodes for a tyrosine phosphatase implicated in the pathogenesis of hematologic malignancies such as Juvenile Myelomonocytic Leukemia (JMML), Acute Myeloid...
UNLABELLED
PTPN11 encodes for a tyrosine phosphatase implicated in the pathogenesis of hematologic malignancies such as Juvenile Myelomonocytic Leukemia (JMML), Acute Myeloid Leukemia (AML), and Acute Lymphoblastic Leukemia (ALL). Since activating mutations of PTPN11 increase proliferative signaling and cell survival through the RAS/MAPK proliferative pathway there is significant interest in using MEK inhibitors for clinical benefit. Yet, single agent clinical activity has been minimal. Previously, we showed that PTPN11 is further activated by upstream tyrosine kinases TNK2/SRC, and that PTPN11-mutant JMML and AML cells are sensitive to TNK2 inhibition using dasatinib. In order to validate these findings, we adopted a genetically engineered mouse model of PTPN11 driven leukemia using the mouse strain 129S/Sv- /Mmucd crossed with B6.129P2- /J. The F1 progeny expressing Ptpn11 within hematopoietic cells destined along the granulocyte-monocyte progenitor lineage developed a fatal myeloproliferative disorder characterized by neutrophilia and monocytosis, and infiltration of myeloid cells into the liver and spleen. Cohorts of Ptpn11 expressing animals treated with combination of dasatinib and trametinib for an extended period of time was well tolerated and had a significant effect in mitigating disease parameters compared to single agents. Finally, a primary patient-derived xenograft model using a myeloid leukemia with PTPN11 F71L also displayed improved disease response to combination. Collectively, these studies point to combined therapies targeting MEK and TNK2/SRC as a promising therapeutic potential for PTPN11-mutant leukemias.
KEY POINTS
Combining MEK and TNK2/SRC inhibitors has therapeutic potential in PTPN11 mutant JMML and AML.
PubMed: 38798550
DOI: 10.1101/2024.05.16.594555 -
Cell Reports. Medicine Jun 2024RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression...
RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.
Topics: Leukemia, Myelomonocytic, Chronic; Myeloid Cell Leukemia Sequence 1 Protein; Humans; Apoptosis; Animals; Mutation; Mice; Signal Transduction; Hematopoietic Stem Cells; Disease Progression; Sulfonamides; NF-kappa B; DNA Methylation; Bridged Bicyclo Compounds, Heterocyclic; Blast Crisis
PubMed: 38781960
DOI: 10.1016/j.xcrm.2024.101585 -
Innere Medizin (Heidelberg, Germany) May 2024The case of a male patient with newly diagnosed polycythemia vera showing rare and unusually rapid progression with phenotypic change towards chronic myelomonocytic...
The case of a male patient with newly diagnosed polycythemia vera showing rare and unusually rapid progression with phenotypic change towards chronic myelomonocytic leukemia is presented. The case report illustrates remarkably rapid disease progression including a structural change in usually indolent polycythemia vera and highlights the prognostic relevance of enhanced molecular genetic testing.
PubMed: 38777881
DOI: 10.1007/s00108-024-01714-2 -
The Journal of General Virology May 2024Porcine reproductive and respiratory syndrome (PRRSV) is an enveloped single-stranded positive-sense RNA virus and one of the main pathogens that causes the most...
Porcine reproductive and respiratory syndrome (PRRSV) is an enveloped single-stranded positive-sense RNA virus and one of the main pathogens that causes the most significant economical losses in the swine-producing countries. PRRSV is currently divided into two distinct species, PRRSV-1 and PRRSV-2. The PRRSV virion envelope is composed of four glycosylated membrane proteins and three non-glycosylated envelope proteins. Previous work has suggested that PRRSV-linked glycans are critical structural components for virus assembly. In addition, it has been proposed that PRRSV glycans are implicated in the interaction with host cells and critical for virus infection. In contrast, recent findings showed that removal of N-glycans from PRRSV does not influence virus infection of permissive cells. Thus, there are not sufficient evidences to indicate compellingly that N-glycans present in the PRRSV envelope play a direct function in viral infection. To gain insights into the role of N-glycosylation in PRRSV infection, we analysed the specific contribution of the envelope protein-linked N-glycans to infection of permissive cells. For this purpose, we used a novel strategy to modify envelope protein-linked N-glycans that consists of production of monoglycosylated PRRSV and viral glycoproteins with different glycan states. Our results showed that removal or alteration of N-glycans from PRRSV affected virus infection. Specifically, we found that complex N-glycans are required for an efficient infection in cell cultures. Furthermore, we found that presence of high mannose type glycans on PRRSV surface is the minimal requirement for a productive viral infection. Our findings also show that PRRSV-1 and PRRSV-2 have different requirements of N-glycan structure for an optimal infection. In addition, we demonstrated that removal of N-glycans from PRRSV does not affect viral attachment, suggesting that these carbohydrates played a major role in regulating viral entry. In agreement with these findings, by performing immunoprecipitation assays and colocalization experiments, we found that N-glycans present in the viral envelope glycoproteins are not required to bind to the essential viral receptor CD163. Finally, we found that the presence of N-glycans in CD163 is not required for PRRSV infection.
Topics: Porcine respiratory and reproductive syndrome virus; Glycosylation; Animals; Swine; Polysaccharides; Porcine Reproductive and Respiratory Syndrome; Viral Envelope Proteins; Cell Line; Receptors, Cell Surface; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Viral Envelope
PubMed: 38776134
DOI: 10.1099/jgv.0.001994 -
Clinical Cancer Research : An Official... May 2024STAT3 is a key transcription factor that mediates cancer progression through phosphorylation or gain-of-function mutations. STAT3 activation in myeloid neoplasms (MNs)...
PURPOSE
STAT3 is a key transcription factor that mediates cancer progression through phosphorylation or gain-of-function mutations. STAT3 activation in myeloid neoplasms (MNs) is primarily mediated through phosphorylation. STAT3 mutation has only rarely been reported in MNs.
EXPERIMENTAL DESIGN
We assessed the clinicopathologic and molecular genetic features of 32 STAT3-mutated MNs.
RESULTS
The frequency of STAT3 mutation in MNs was <0.5%. Twenty (62.5%) cases were classified as acute myeloid leukemia (AML), 7 (21.9%) as myelodysplastic syndrome (MDS), 5 (15.6%) as chronic myelomonocytic leukemia (CMML), but none as myeloproliferative neoplasms (MPN). STAT3 mutations occurred at initial diagnosis in 22 (88%) cases, or at relapse or upon leukemic transformation. Clonal hierarchy analysis revealed that STAT3 mutations represented the dominant clone in 30% of AML cases, but were subclonal in MDS and CMML. Most were missense mutations located at the SH2 domain, Y640F being the most common. STAT3 mutation was accompanied by co-existing mutations in all cases, most frequently SRSF2, TET2, ASXL1, and SETBP1. STAT3 mutations were usually associated with morphologic dysplasia, increased blasts, and monosomy 7/del7q. With a median follow-up of 24.5 months, 21 patients died, 6 had persistent disease, and 5 achieved complete remission after stem cell transplantation.
CONCLUSIONS
STAT3 mutation is present in various MNs, but not in MPN. It is often an early event or occurs upon leukemic transformation, suggesting an important role in the pathogenesis and progression of MNs by activating JAK-STAT pathway. It may help identify a subset of patients with MNs who may benefit from targeted therapy.
PubMed: 38767620
DOI: 10.1158/1078-0432.CCR-24-0066 -
Indian Journal of Ophthalmology May 2024To investigate the histopathological findings of the anterior lens capsule in pediatric patients who had surgery for cataracts.
PURPOSE
To investigate the histopathological findings of the anterior lens capsule in pediatric patients who had surgery for cataracts.
METHODS
This study is a prospective interventional study. Anterior capsule tissue samples that were obtained by the anterior capsulotomy method during phacoemulsification surgery were fixed and examined under a transmission electron microscope.
RESULTS
Twenty-two eyes of 19 patients who were diagnosed with congenital and juvenile cataracts were included in this study. Five patients had associated systemic diseases, including hydrocephalus, cerebral palsy, prematurity, juvenile myelomonocytic leukemia, and Down's syndrome. Electron microscopic evaluation demonstrated single-layered epithelium under the capsule, degenerated organelles with round-oval and prismatic-oval nuclei, and degenerated mitochondria and heterochromatin-rich nuclei. In the case with cerebral palsy, collagen fibrils of the connective tissue and fibroblast-like cells were observed replacing the epithelium that should be underneath the capsule in both eyes, and there was a disorganized distribution of collagen fibrils and vacuole structures in the cytoplasm of fibroblast-like cells.
CONCLUSION
Similar histopathological findings were found in pediatric cataracts with or without systemic disease except in one cerebral palsy case. The absence of lens epithelium may have been a result of degeneration in this patient, and this can be attributed to the presence of systemic inflammation and gliosis in cerebral palsy. The absence of lens epithelium can play a role in the development of dense subcapsular fibrosis and cataract formation.
PubMed: 38767535
DOI: 10.4103/IJO.IJO_2957_23