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Cellular Signalling Mar 2012The multidomain protein Vav1, in addition to promote the acquisition of maturation related properties by normal hematopoietic cells, is a key player in the ATRA- and... (Review)
Review
The multidomain protein Vav1, in addition to promote the acquisition of maturation related properties by normal hematopoietic cells, is a key player in the ATRA- and PMA-induced completion of the differentiation program of tumoral myeloid precursors derived from APL. This review is focussed on the role of Vav1 in differentiating promyelocytes, as part of interconnected networks of functionally related proteins ended to regulate different aspects of myeloid maturation. The role of Vav1 in determining actin cytoskeleton reorganization alternative to the best known function as a GEF for small G proteins is discussed, as well as the binding of Vav1 with cytoplasmic and nuclear signaling molecules which provides a new perspective in the modulation of nuclear architecture and activity. In particular, new hints are provided on the ability of Vav1 to determine the nuclear amount of proteins implicated in modulating mRNA production and stability and in regulating the ATRA-dependent protein expression also by direct interaction with transcription factors known to drive the ATRA-induced maturation of myeloid cells. The reviewed findings summarize the major advances in the understanding of additional, non conventional functions connected with the vast interactive potential of Vav1.
Topics: Actin Cytoskeleton; Cell Differentiation; Cell Nucleus; DNA-Binding Proteins; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Proto-Oncogene Proteins c-vav; RNA, Messenger; Transcription Factors
PubMed: 22133616
DOI: 10.1016/j.cellsig.2011.11.017 -
Immunity Aug 2020Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes....
Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes. Although studies have proposed lineage heterogeneity within GMPs, it is unclear if committed progenitors already exist among these progenitors and how they may behave differently during inflammation. By combining single-cell transcriptomic and proteomic analyses, we identified the early committed progenitor within the GMPs responsible for the strict production of neutrophils, which we designate as proNeu1. Our dissection of the GMP hierarchy led us to further identify a previously unknown intermediate proNeu2 population. Similar populations could be detected in human samples. proNeu1s, but not proNeu2s, selectively expanded during the early phase of sepsis at the expense of monocytes. Collectively, our findings help shape the neutrophil maturation trajectory roadmap and challenge the current definition of GMPs.
Topics: Animals; Granulocyte Precursor Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Myelopoiesis; Neutrophils; Single-Cell Analysis
PubMed: 32579887
DOI: 10.1016/j.immuni.2020.06.005 -
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 -
Best Practice & Research. Clinical... Sep 2003Evaluation of cell morphology is usually sufficient to diagnose acute promyelocytic leukaemia (APL). In this chapter we discuss the features of classical hypergranular... (Review)
Review
Evaluation of cell morphology is usually sufficient to diagnose acute promyelocytic leukaemia (APL). In this chapter we discuss the features of classical hypergranular APL, the APL variant, hyperbasophilic promyelocytic leukaemia, APL with basophil-like granules, acute eosinophilic leukaemia with PML/RARalpha positivity and the morphology of APL cells lacking t(15;17). In addition to morphological examination, cytochemical investigations (peroxidase chloroacetate-esterase, etc.) may help further in defining the cytology of leukaemic cells in APL.
Topics: Cell Size; Granulocyte Precursor Cells; Humans; Immunohistochemistry; Intracellular Space; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute
PubMed: 12935955
DOI: 10.1016/s1521-6926(03)00061-6 -
British Journal of Haematology Nov 2022
Topics: Humans; Leukemia, Promyelocytic, Acute; Granulocyte Precursor Cells; Leukocyte Count
PubMed: 35996972
DOI: 10.1111/bjh.18428 -
Immunity Nov 2017Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during...
Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during infection. Both progenitor populations are thought to derive from common myeloid progenitors (CMPs), and a hierarchical relationship (CMP-GMP-MDP-monocyte) is presumed to underlie monocyte differentiation. Here, however, we demonstrate that mouse MDPs arose from CMPs independently of GMPs, and that GMPs and MDPs produced monocytes via similar but distinct monocyte-committed progenitors. GMPs and MDPs yielded classical (Ly6C) monocytes with gene expression signatures that were defined by their origins and impacted their function. GMPs produced a subset of "neutrophil-like" monocytes, whereas MDPs gave rise to a subset of monocytes that yielded monocyte-derived dendritic cells. GMPs and MDPs were also independently mobilized to produce specific combinations of myeloid cell types following the injection of microbial components. Thus, the balance of GMP and MDP differentiation shapes the myeloid cell repertoire during homeostasis and following infection.
Topics: Animals; Antigens, Ly; Cell Differentiation; Dendritic Cells; Granulocyte Precursor Cells; Leukosialin; Mice; Monocytes; Myeloid Progenitor Cells; Sequence Analysis, RNA; Transcriptome
PubMed: 29166589
DOI: 10.1016/j.immuni.2017.10.021 -
Best Practice & Research. Clinical... Mar 2014If looking for a mnemonic to remember the relevant facts about acute promyelocytic leukemia (APL), one just has to remember that APL is a disease of A's. It is acute and... (Review)
Review
If looking for a mnemonic to remember the relevant facts about acute promyelocytic leukemia (APL), one just has to remember that APL is a disease of A's. It is acute and it is highly sensitive to treatment with anthracyclines, all-trans-retinoic acid (RA) and arsenic trioxide (ATO). The presence of fusions involving the retinoic acid receptor alpha (RARA) is without question the central player driving APL and dictating the response of this disease to these therapeutic agents. However, beyond this knowledge, the molecular mechanisms that contribute to the complicated pathogenesis and the response to treatment of APL are not completely defined. As more is understood about this hematological malignancy, there are more opportunities to refine and improve treatment based on this knowledge. In this review article, we discuss the response of APL to these "A" therapies.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Topoisomerase II Inhibitors; Transcription, Genetic; Tretinoin
PubMed: 24907014
DOI: 10.1016/j.beha.2014.04.009 -
Genes Mar 2023Acute promyelocytic leukemia (APL) pathogenesis is based on gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL....
Acute promyelocytic leukemia (APL) pathogenesis is based on gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL. However, in some cases acute myeloid leukemia (AML) demonstrates APL-like morphological features such as atypical promyelocytes accumulation. This type of AML is characterized by the involvement of other family members or completely different genes. In the present study, we used conventional karyotyping, FISH and high-throughput sequencing in a group of 271 de novo AML with atypical promyelocytes accumulation. Of those, 255 cases were shown to carry a typical chromosomal translocation t(15;17)(q24;q21) with chimeric gene formation (94.1%). Other -positive cases exhibited cryptic fusion without t(15;17)(q24;q21) (1.8%, = 5) and variant t(5;17)(q35;q21) translocation with chimeric gene formation (1.5%, = 4). However, 7 -negative AMLs with atypical promyelocytes accumulation were also discovered. These cases exhibited and fusions as well as mutations, e.g., insertion and non-recurrent chromosomal aberrations. Our findings demonstrate the genetic diversity of AML with APL-like morphological features, which is of high importance for successful therapy implementation.
Topics: Humans; Granulocyte Precursor Cells; Leukemia, Promyelocytic, Acute; Leukemia, Myeloid, Acute; Translocation, Genetic; Nuclear Proteins
PubMed: 36980947
DOI: 10.3390/genes14030675 -
Journal of Nippon Medical School =... Mar 2021Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical...
BACKGROUND
Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is needed.
METHODS
This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 10 CD34-positive cells/kg (range: 0.3-47.4 × 10 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 10 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed.
RESULTS
The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 [72.3%] vs. n = 11 [44.0%] in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 10/μL; range: 1.60-47.4 × 10 cells/μL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment.
CONCLUSION
The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.
Topics: Adolescent; Adult; Aged; Antigens, CD34; Female; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Lymphoma; Male; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Peripheral Blood Stem Cells; Retrospective Studies; Time Factors; Tissue and Organ Harvesting; Transplantation, Autologous; Young Adult
PubMed: 32238739
DOI: 10.1272/jnms.JNMS.2021_88-104 -
Blood Nov 2013
Topics: Blood Cell Count; Chediak-Higashi Syndrome; Cytoplasmic Granules; Diagnosis, Differential; Disseminated Intravascular Coagulation; Female; Granulocyte Precursor Cells; Humans; Middle Aged
PubMed: 24354010
DOI: 10.1182/blood-2013-06-507400