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Nature Reviews. Disease Primers Oct 2021The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological... (Review)
Review
The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207 antigen with physiological epidermal Langerhans cells. LCH, Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. 'Inflammatory myeloproliferative neoplasm' may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.
Topics: Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Inflammation; Xanthogranuloma, Juvenile
PubMed: 34620874
DOI: 10.1038/s41572-021-00307-9 -
Acta Pharmaceutica Sinica. B Apr 2021The initiation and development of major inflammatory diseases, , cancer, vascular inflammation, and some autoimmune diseases are closely linked to the immune system.... (Review)
Review
The initiation and development of major inflammatory diseases, , cancer, vascular inflammation, and some autoimmune diseases are closely linked to the immune system. Biologics-based immunotherapy is exerting a critical role against these diseases, whereas the usage of the immunomodulators is always limited by various factors such as susceptibility to digestion by enzymes , poor penetration across biological barriers, and rapid clearance by the reticuloendothelial system. Drug delivery strategies are potent to promote their delivery. Herein, we reviewed the potential targets for immunotherapy against the major inflammatory diseases, discussed the biologics and drug delivery systems involved in the immunotherapy, particularly highlighted the approved therapy tactics, and finally offer perspectives in this field.
PubMed: 33996408
DOI: 10.1016/j.apsb.2020.12.018 -
Cell Aug 2020Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits...
Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2 mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1 and CXCR1 macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.
Topics: Animals; Antibodies, Monoclonal; CX3C Chemokine Receptor 1; Cell Line, Tumor; Disease Models, Animal; Humans; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Membrane Glycoproteins; Methylcholanthrene; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Prognosis; Programmed Cell Death 1 Receptor; Receptors, Immunologic; Tumor Microenvironment
PubMed: 32783918
DOI: 10.1016/j.cell.2020.07.013 -
Annals of Hematology Aug 2023Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow,... (Review)
Review
Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow, in most cases concomitant with acute myeloid leukaemia (AML), rarely without bone marrow involvement. MS may also represent the blast phase of chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). However, the clinical and molecular heterogeneity of AML, as highlighted by the 2022 World Health Organization (WHO) and International Consensus (ICC) classifications, indirectly define MS more as a set of heterogeneous and proteiform diseases, rather than a homogeneous single entity. Diagnosis is challenging and relies mainly on histopathology, immunohistochemistry, and imaging. Molecular and cytogenetic analysis of MS tissue, particularly in isolated cases, should be performed to refine the diagnosis, and thus assign prognosis guiding treatment decisions. If feasible, systemic therapies used in AML remission induction should be employed, even in isolated MS. Role and type of consolidation therapy are not univocally acknowledged, and systemic therapies, radiotherapy, or allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be considered. In the present review, we discuss recent information on MS, focusing on diagnosis, molecular findings, and treatments also considering targetable mutations by recently approved AML drugs.
Topics: Humans; Sarcoma, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 37286874
DOI: 10.1007/s00277-023-05288-1 -
Acta Pharmaceutica Sinica. B Oct 2021Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic... (Review)
Review
Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.
PubMed: 34729299
DOI: 10.1016/j.apsb.2021.01.003 -
Acta Pharmaceutica Sinica. B Jan 2021Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in... (Review)
Review
Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.
PubMed: 33532178
DOI: 10.1016/j.apsb.2020.07.010 -
Pathobiology : Journal of... 2024Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether... (Review)
Review
Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether referred to as myeloid neoplasms (MN), is a major source of mortality. Apart from transformation to acute myeloid leukemia, the clinical progression of MN is mostly due to the overgrowth of pre-existing hematopoiesis by the MN without an additional transforming event. Still, MN may evolve along other recurrent yet less well-known scenarios: (1) acquisition of MPN features in MDS or (2) MDS features in MPN, (3) progressive myelofibrosis (MF), (4) acquisition of chronic myelomonocytic leukemia (CMML)-like characteristics in MPN or MDS, (5) development of myeloid sarcoma (MS), (6) lymphoblastic (LB) transformation, (7) histiocytic/dendritic outgrowths. These MN-transformation types exhibit a propensity for extramedullary sites (e.g., skin, lymph nodes, liver), highlighting the importance of lesional biopsies in diagnosis. Gain of distinct mutations/mutational patterns seems to be causative or at least accompanying several of the above-mentioned scenarios. MDS developing MPN features often acquire MPN driver mutations (usually JAK2), and MF. Conversely, MPN gaining MDS features develop, e.g., ASXL1, IDH1/2, SF3B1, and/or SRSF2 mutations. Mutations of RAS-genes are often detected in CMML-like MPN progression. MS ex MN is characterized by complex karyotypes, FLT3 and/or NPM1 mutations, and often monoblastic phenotype. MN with LB transformation is associated with secondary genetic events linked to lineage reprogramming leading to the deregulation of ETV6, IKZF1, PAX5, PU.1, and RUNX1. Finally, the acquisition of MAPK-pathway gene mutations may shape MN toward histiocytic differentiation. Awareness of all these less well-known MN-progression types is important to guide optimal individual patient management.
Topics: Humans; Granulocyte Precursor Cells; Myeloproliferative Disorders; Myelodysplastic Syndromes; Mutation; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid, Acute
PubMed: 37232015
DOI: 10.1159/000530940 -
Blood Feb 2021Mutations of the nucleophosmin (NPM1) gene, encoding for a nucleolar multifunctional protein, occur in approximately one-third of adult acute myeloid leukemia (AML)....
Mutations of the nucleophosmin (NPM1) gene, encoding for a nucleolar multifunctional protein, occur in approximately one-third of adult acute myeloid leukemia (AML). NPM1-mutated AML exhibits unique molecular, pathological, and clinical features, which led to its recognition as distinct entity in the 2017 World Health Organization (WHO) classification of myeloid neoplasms. Although WHO criteria for the diagnosis of NPM1-mutated AML are well established, its distinction from other AML entities may be difficult. Moreover, the percentage of blasts required to diagnose NPM1-mutated AML remains controversial. According to the European LeukemiaNet (ELN), determining the mutational status of NPM1 (together with FLT3) is mandatory for accurate relapse-risk assessment. NPM1 mutations are ideal targets for measurable residual disease (MRD) monitoring, since they are AML specific, frequent, very stable at relapse, and do not drive clonal hematopoiesis of undetermined significance. MRD monitoring by quantitative polymerase chain reaction of NPM1-mutant transcripts, possibly combined with ELN genetic-based risk stratification, can guide therapeutic decisions after remission. Furthermore, immunohistochemistry can be very useful in selected situations, such as diagnosis of NPM1-mutated myeloid sarcoma. Herein, we present 4 illustrative cases of NPM1-mutated AML that address important issues surrounding the biology, diagnosis, and therapy of this common form of leukemia.
Topics: Age Factors; Aged; Algorithms; Allografts; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Cell Lineage; Clinical Trials as Topic; Clonal Evolution; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Female; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Myelodysplastic Syndromes; Neoplastic Stem Cells; Nuclear Proteins; Nucleophosmin; Oncogene Proteins, Fusion; Patient Selection; Practice Patterns, Physicians'; Remission Induction; Risk Assessment; Salvage Therapy; Sulfonamides; fms-Like Tyrosine Kinase 3
PubMed: 33171486
DOI: 10.1182/blood.2020008211 -
Cureus Dec 2020Chloromas are an atypical cellular infiltrate of immature granulocytic cells that can occur specially in patients with acute myelogenous leukemia (AML), but can be...
Chloromas are an atypical cellular infiltrate of immature granulocytic cells that can occur specially in patients with acute myelogenous leukemia (AML), but can be present in nonleukemic patients. Its clinical course will be dependent on its size and location, from asymptomatic to simulating a malignant gastrointestinal neoplasia. Definitive diagnosis is made upon an immunoprofile that is similar to that present in the blasts and precursor cells of acute myeloid leukemia. Endoscopic and CT images are variable being only part of the protocol panel. Treatment is the same as to AML, but surgery and radiation must be used in order to maintain low relapse and better overall survival.
PubMed: 33489498
DOI: 10.7759/cureus.12080