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Haematologica May 2020The bone marrow niche is a complex and dynamic structure composed of a multitude of cell types which functionally create an interactive network facilitating... (Review)
Review
The bone marrow niche is a complex and dynamic structure composed of a multitude of cell types which functionally create an interactive network facilitating hematopoietic stem cell development and maintenance. Its specific role in the pathogenesis, response to therapy, and transformation of myeloproliferative neoplasms has only recently been explored. Niche functionality is likely affected not only by the genomic background of the myeloproliferative neoplasm-associated mutated hematopoietic stem cells, but also by disease-associated 'chronic inflammation', and subsequent adaptive and innate immune responses. 'Cross-talk' between mutated hematopoietic stem cells and multiple niche components may contribute to propagating disease progression and mediating drug resistance. In this timely article, we will review current knowledge surrounding the deregulated bone marrow niche in myeloproliferative neoplasms and suggest how this may be targeted, either directly or indirectly, potentially influencing therapeutic choices both now and in the future.
Topics: Bone Marrow; Hematopoietic Stem Cells; Humans; Myeloproliferative Disorders; Neoplasms; Stem Cell Niche
PubMed: 32241851
DOI: 10.3324/haematol.2019.243121 -
Journal of Cellular and Molecular... Sep 2017A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result... (Review)
Review
A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result of combined genetic dysregulation, with several mutated genes involved in the regulation of epigenetic mechanisms. Epigenetic changes are not due to a change in the DNA sequence but are reversible modifications that dictate the way in which genes may be expressed (or silenced). Among the epigenetic mechanisms, DNA methylation is probably the best described. Currently known MPN-associated mutations now include JAK2, MPL, LNK, CBL, CALR, TET2, ASXL1, IDH1, IDH2, IKZF1 and EZH2. Enhancing our knowledge about the mutation profile of patients may allow them to be stratified into risk groups which would aid clinical decision making. Ongoing work will answer whether the use of epigenetic therapies as alterative pathway targets in combination with JAK inhibitors may be more effective than single agent treatment.
Topics: Chromatin; DNA Methylation; Epigenesis, Genetic; Humans; MicroRNAs; Mutation; Myeloproliferative Disorders
PubMed: 28677265
DOI: 10.1111/jcmm.13095 -
International Journal of Molecular... May 2022There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in... (Review)
Review
There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in treating -) myeloproliferative neoplasm (MPN). To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1 promoter, which are as follows: (a) the extrinsic mechanism, which is activated by interferon gamma (IFN γ) by tumor infiltration lymphocytes (TIL) and NK cells; (b) the intrinsic mechanism of EGFR or PTEN loss resulting in the activation of the MAPK and AKT pathways and then stat 1 and 3 activation; and (c) 9p24 amplicon amplification, resulting in PD-L1 and Jak2 activation. We also review the literature and postulate that many of the failures of CPI therapy in MPN are likely due to excessive MDSC activities. We list all of the anti-MDSC agents, especially those with ruxolitinib, IMID compounds, and BTK inhibitors, which may be combined with CPI therapy in the future as part of clinical trials applying CPI therapy to (-) MPN.
Topics: B7-H1 Antigen; Humans; Myeloid-Derived Suppressor Cells; Myeloproliferative Disorders; Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 35628647
DOI: 10.3390/ijms23105837 -
Blood Cancer Journal Nov 2018Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The... (Review)
Review
Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The clinical picture is heterogeneous, ranging from isolated thrombocytosis, mimicking essential thrombocythemia (ET), to symptoms of high-risk PMF. Retrospective studies showed that survival of patients with pre-PMF is worse than that of ET and better than overt PMF. Whilst a specific prognostic score is lacking, the International Prognostic Scoring System is able to predict survival in pre-PMF patients, yet failing to separate intermediate-1 and -2 groups, and can be used in clinical practice. Each patient should be evaluated for, and interventions adapted to, both life-expectancy and the risk of bleeding and thrombosis. In low-risk patients with expected long survival, observation only is recommended; in cumulated intermediate-1 and -2 risk cases, whose median survival is projected at more than 10 years, treatment is based on symptoms; in high risk cases, with median survival lower than 5 years, intensive management is required. A pragmatic approach to address the risk of bleeding and thrombosis includes: no treatment or low-dose aspirin in asymptomatic patients; aspirin or oral anticoagulation if previous arterial or venous thrombosis, and hydroxyurea as first-line cytoreduction in case of thrombocytosis or leukocytosis.
Topics: Algorithms; Animals; Biomarkers; Disease Management; Female; Humans; Male; Mutation; Myeloproliferative Disorders; Outcome Assessment, Health Care; Phenotype; Primary Myelofibrosis; Risk Assessment; Risk Factors; Thrombocythemia, Essential
PubMed: 30405096
DOI: 10.1038/s41408-018-0142-z -
American Journal of Hematology Apr 2023
Topics: Humans; Blast Crisis; Myeloproliferative Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 36655312
DOI: 10.1002/ajh.26849 -
Blood Dec 2017Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago... (Review)
Review
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
Topics: Animals; Cell Transformation, Neoplastic; Clonal Evolution; Disease Progression; Epistasis, Genetic; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Janus Kinases; Mutation; Myeloproliferative Disorders; Phenotype; STAT Transcription Factors; Signal Transduction
PubMed: 29212804
DOI: 10.1182/blood-2017-06-782037 -
Hematology. American Society of... Dec 2017Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago... (Review)
Review
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
Topics: Animals; DNA Mutational Analysis; Hematologic Neoplasms; Humans; Janus Kinase 2; Mutation; Myelopoiesis; Myeloproliferative Disorders; Protein Kinase Inhibitors
PubMed: 29222295
DOI: 10.1182/asheducation-2017.1.470 -
International Journal of Molecular... Mar 2021mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary... (Review)
Review
mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary myelofibrosis. To date, several mutations were identified, with only frameshift mutations linked to the diseased phenotype. It is of diagnostic and prognostic importance to properly define the type of mutation and subclassify it according to its structural similarities to the classical mutations, a 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2 mutation), using a statistical approximation algorithm (AGADIR). Today, the knowledge on the pathogenesis of -positive MPN is expanding and several cellular mechanisms have been recognized that finally cause a clonal hematopoietic expansion. In this review, we discuss the current basis of the cellular effects of mutants and the understanding of its implementation in the current diagnostic laboratorial and medical practice. Different methods of detection are explained and a diagnostic algorithm is shown that aids in the approach to -positive MPN. Finally, contemporary methods joining artificial intelligence in accordance with molecular-genetic biomarkers in the approach to MPN are presented.
Topics: Algorithms; Animals; Artificial Intelligence; Biomarkers; Calreticulin; DNA Mutational Analysis; Gene Deletion; Hematology; Humans; Ligands; Machine Learning; Molecular Chaperones; Mutation; Myeloproliferative Disorders; Phenotype; Prognosis; Signal Transduction; Thrombocytosis
PubMed: 33806036
DOI: 10.3390/ijms22073371 -
Best Practice & Research. Clinical... Mar 2021Myeloproliferative neoplasm-blast phase (MPN-BP) is a form of acute leukemia which is distinct from de novo acute myeloid leukemia with each entity being characterized... (Review)
Review
Myeloproliferative neoplasm-blast phase (MPN-BP) is a form of acute leukemia which is distinct from de novo acute myeloid leukemia with each entity being characterized by specific complex cytogenetic abnormalities and myeloid gene mutational patterns. MPN-BP patients have a particularly dismal prognosis with a medium overall survival of 5.8 months with currently available therapies. Large-scale sequencing studies have unraveled the mutational landscape of the chronic MPNs and MPN-BP, demonstrating importance of clonal heterogeneity and the role of somatic mutations in disease progression and their use to determine patient outcomes. JAK inhibitors represent the standard of care for intermediate/high-risk MF patients and have been shown to improve clinical symptoms. However, this therapeutic approach leads to a modest reduction in the variant allele frequency of the known MPN driver mutations in most patients and does not substantially delay or prevent the evolution to MPN-BP. In this article, we will review molecular mechanisms driving the progression from chronic MPNs to a BP, the impact of genetic changes on MPN-BP evolution, and the role of clonal evolution in response to JAK inhibitor therapy and disease progression. We will also discuss our ongoing functional studies of cells responsible for the development of MPN-BP.
Topics: Blast Crisis; Clonal Evolution; Humans; Leukemia, Myeloid, Acute; Mutation; Myeloproliferative Disorders
PubMed: 33762108
DOI: 10.1016/j.beha.2021.101254 -
Pathobiology : Journal of... 2019The updated 2016 WHO classification of hematopoietic tumors has a new category: "myeloid neoplasms with germline predisposition." These entities are rare, but are also... (Review)
Review
The updated 2016 WHO classification of hematopoietic tumors has a new category: "myeloid neoplasms with germline predisposition." These entities are rare, but are also currently underdiagnosed and underreported. Recognition is critical for appropriate clinical evaluation and therapy, with potential implications for the patient's entire family. The WHO includes 3 categories of myeloid neoplasms with germline predisposition: neoplasms without preexisting conditions, neoplasms with a history of thrombocytopenia, and neoplasms with other organ dysfunction. Specialized molecular testing is frequently necessary to make the diagnosis, as the presence of one of the implicated mutations is not sufficient for diagnosis and should be confirmed with germline DNA evaluation. Many families have unique mutations that are not detected by targeted sequencing panels. Periodic bone marrow (BM) examinations are recommended to assess patients' baseline morphology and rule out evidence of disease progression. Thus, accurate diagnosis requires a careful recording of clinical history, a BM morphology evaluation, and advanced molecular testing.
Topics: Bone Marrow Examination; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Humans; Mutation; Myeloproliferative Disorders; Pathology, Molecular
PubMed: 30048985
DOI: 10.1159/000490311