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Clinical Lymphoma, Myeloma & Leukemia Aug 2016Currently, prognostication in primary myelofibrosis (PMF) relies on the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus, which... (Review)
Review
Currently, prognostication in primary myelofibrosis (PMF) relies on the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus, which incorporate age, blood counts, constitutional symptoms, circulating blasts, red cell transfusion need, and karyotype. Although the JAK2 V617F mutation was discovered a decade ago and MPL mutations shortly thereafter, it was the recent discovery of CALR mutations in the vast majority of JAK2/MPL-unmutated patients and recognition of the powerful impact of CALR mutations and triple-negative (JAK2/MPL/CALR-negative) status on outcome that set the stage for revision of traditional prognostic models to include molecular information. Additionally, the advent of next-generation sequencing has identified a host of previously unrecognized somatic mutations across hematologic malignancies. As in the myelodysplastic syndromes, the majority of common and prognostically informative mutations in PMF affect epigenetic regulation and mRNA splicing. Thus, a need has arisen to incorporate mutational information on genes such as ASXL1 and SRSF2 into risk stratification systems. Mutations in yet other genes appear to be important players in leukemic transformation, and new insights into disease pathogenesis are emerging. Finally, the number of prognostically detrimental mutations may affect both survival and response to ruxolitinib, which has significant implications for clinical decision making. In this review, we briefly summarize the prognostic models in use today and discuss in detail the somatic mutations commonly encountered in patients with PMF, along with their prognostic implications and role in leukemic transformation. Emerging prognostic models that incorporate new molecular information into existing systems or exclude clinical variables are also presented.
Topics: Cell Transformation, Neoplastic; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Genomics; Humans; Mutation; Myeloproliferative Disorders; Philadelphia Chromosome; Primary Myelofibrosis; Prognosis; RNA Splicing; Risk Factors
PubMed: 27521306
DOI: 10.1016/j.clml.2016.02.031 -
Experimental Hematology Dec 2021Single-cell technologies have rapidly developed in recent years and have already had a significant impact on the research of myeloproliferative neoplasms. The increasing... (Review)
Review
Single-cell technologies have rapidly developed in recent years and have already had a significant impact on the research of myeloproliferative neoplasms. The increasing number of publicly available data sets allows characterization of the bone marrow niche in patients and mouse models at unprecedented resolution. Single-cell RNA sequencing has successfully been used to identify and characterize disease-driving cell populations and to identify the alarmin S100A8/A9 as an important mediator of myelofibrosis and potent therapeutic target. It is now possible to execute a streamlined set of experiments to specifically identify and validate actionable target genes functionally with the advance of reliable in vivo models and the possibility of conducting single-cell analyses with a minimal amount of patient material. The advent of large-scale analyses of both hematopoietic and non-hematopoietic bone marrow cells will allow comprehensive network analyses guiding an increasingly detailed mapping of the MPN interactome.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Disease Models, Animal; Gene Expression Profiling; Humans; Primary Myelofibrosis; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome; Translational Research, Biomedical
PubMed: 34601067
DOI: 10.1016/j.exphem.2021.09.006 -
International Journal of Molecular... Oct 2023Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the... (Review)
Review
Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the general population of 1-2%. An episode of seemingly unprovoked SVT almost always triggers a diagnostic work-up for a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), since atypical site thrombosis is a hallmark of MPN-associated thrombophilia. Primary myelofibrosis (PMF) is a rare MPN with an estimated incidence between 0.1 and 1/100,000 per year. Although prothrombotic tendency in PMF is not envisioned as a subject of specific therapeutic management, unlike other MPNs, such as polycythemia vera (PV) and essential thrombocythemia (ET), thrombotic risk and SVT prevalence in PMF may be comparably high. Additionally, unlike PV and ET, SVT development in PMF may depend more on procoagulant mechanisms involving endothelium than on blood cell activation. Emerging results from registry data also suggest that PMF patients with SVT may exhibit lower risk and better prognosis, thus highlighting the need for better thrombotic risk stratification and identifying a subset of patients with potential benefit from antithrombotic prophylaxis. This review highlights specific epidemiological, pathogenetic, and clinical features pertinent to SVT in myelofibrosis.
Topics: Humans; Primary Myelofibrosis; Myeloproliferative Disorders; Venous Thrombosis; Polycythemia Vera; Thrombosis; Thrombocythemia, Essential; Phenotype
PubMed: 37958701
DOI: 10.3390/ijms242115717 -
American Journal of Hematology Sep 2022
Topics: Humans; Mutation; Phosphoproteins; Primary Myelofibrosis; Prognosis; RNA Splicing Factors
PubMed: 35796725
DOI: 10.1002/ajh.26648 -
Acta Clinica Belgica Apr 2015To date, only a small number of epidemiological studies on myelofibrosis have been performed. The current study aimed to characterize the myelofibrosis patient...
OBJECTIVE
To date, only a small number of epidemiological studies on myelofibrosis have been performed. The current study aimed to characterize the myelofibrosis patient population in Belgium according to pre-defined disease parameters (diagnosis, risk categories, hemoglobin <10 g/dl, spleen size, constitutional symptoms, platelet count, myeloblast count), with a view to obtaining a deeper understanding of the proportion of patients that may benefit from the novel myelofibrosis therapeutic strategies.
METHODS
A survey was used to collect data on prevalence and disease parameters on all myelofibrosis patients seen at each of 18 participating hematologic centers in 2011. Aggregated data from all centers were used for analysis. Analyses were descriptive and quantitative.
RESULTS
A total of 250 patients with myelofibrosis were captured; of these, 136 (54%) were male and 153 (61%) were over 65 years old. One hundred sixty-five (66%) of myelofibrosis patients had primary myelofibrosis and 85 (34%) had secondary myelofibrosis. One hundred ninety-three myelofibrosis patients (77%) had a palpable spleen. About a third of patients (34%) suffered from constitutional symptoms. Two hundred twenty-two (89%) myelofibrosis patients had platelet count ≧50 000/μl and 201 (80%) had platelet count ≧100 000/μl. Of 250 patients, 85 (34%) had a myeloblast count ≧1%. Six (2%) patients had undergone a splenectomy. Thirteen (5·2%) patients had undergone radiotherapy for splenomegaly.
CONCLUSIONS
The results of this survey provide insight into the characteristics of the Belgian myelofibrosis population. They also suggest that a large proportion of these patients could stand to benefit from the therapies currently under development.
Topics: Aged; Belgium; Cohort Studies; Female; Humans; Male; Middle Aged; Platelet Count; Prevalence; Primary Myelofibrosis
PubMed: 25380026
DOI: 10.1179/2295333714Y.0000000097 -
Leukemia Apr 2023In this Perspective, we discuss criteria for defining a new disease entity or variant of a recognized disease or disorder. We do so in the context of the current... (Review)
Review
In this Perspective, we discuss criteria for defining a new disease entity or variant of a recognized disease or disorder. We do so in the context of the current topography of the BCR::ABL-negative myeloproliferative neoplasms (MPNs) where two new variants are reported: clonal megakaryocyte dysplasia with normal blood values (CMD-NBV) and clonal megakaryocyte dysplasia with isolated thrombocytosis (CMD-IT). The cardinal feature of these variants is bone marrow megakaryocyte hyperplasia and atypia corresponding the WHO histological criteria for primary myelofibrosis (myelofibrosis-type megakaryocyte dysplasia-MTMD). Persons with these new variants have a different disease course and features from others in the MPN domain. In a broader context we suggest myelofibrosis-type megakaryocyte dysplasia defines a spectrum of related MPN variants including CMD-NBV, CMD-IT, pre-fibrotic myelofibrosis and overt myelofibrosis, which differ from polycythemia vera and essential thrombocythemia. Our proposal needs external validation and we stress the need for a consensus definition of the megakaryocyte dysplasia which is the hallmark of these disorders.
Topics: Humans; Bone Marrow Diseases; Megakaryocytes; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocytosis; Fusion Proteins, bcr-abl
PubMed: 36871061
DOI: 10.1038/s41375-023-01861-9 -
Cells Jul 2022Myelofibrosis (MF) is the most symptomatic form of myeloproliferative neoplasm and carries the worst outcome. Allogeneic hematopoietic stem cell transplantation is the... (Review)
Review
Myelofibrosis (MF) is the most symptomatic form of myeloproliferative neoplasm and carries the worst outcome. Allogeneic hematopoietic stem cell transplantation is the only therapy with potential for cure at present, but is limited by significant mortality and morbidity. JAK inhibition is the mainstay of treatment for intermediate- and high-risk MF. Ruxolitinib is the most widely used JAK1/2 inhibitor and provides durable effects in controlling symptom burden and spleen volumes. Nevertheless, ruxolitinib may not adequately address the underlying disease biology. Its effects on mutant allele burden, bone marrow fibrosis, and the prevention of leukemic transformation are minimal. Multiple small molecules are being tested in multiple phase 2 and 3 studies as either monotherapy or in combination with JAK2 inhibitors. In this review, the role of LSD1/KDM1A inhibition as a potential disease-modification strategy in patients with myelofibrosis is described and discussed.
Topics: Hematopoietic Stem Cell Transplantation; Histone Demethylases; Humans; Lysine; Myeloproliferative Disorders; Primary Myelofibrosis
PubMed: 35805191
DOI: 10.3390/cells11132107 -
Blood Feb 2023Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by the clonal expansion of myeloid cells, notably megakaryocytes (MKs), and an aberrant...
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by the clonal expansion of myeloid cells, notably megakaryocytes (MKs), and an aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-β1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-β1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-β1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-β1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found an increased expression of GARP in the BM and spleen of mice with PMF and tested the therapeutic potential of a monoclonal antibody (mAb) that blocks TGF-β1 activation by GARP-expressing cells. GARP:TGF-β1 blockade reduced not only fibrosis but also the clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-β1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-γ signals in the spleen, were lost upon CD8 T-cell depletion. Our results suggest that the selective blockade of TGF-β1 activation by GARP-expressing Tregs increases a CD8 T-cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.
Topics: Mice; Animals; Transforming Growth Factor beta1; Primary Myelofibrosis; Antibodies, Monoclonal; Cytokines; Fibrosis; T-Lymphocytes, Regulatory
PubMed: 36322928
DOI: 10.1182/blood.2022017097 -
Einstein (Sao Paulo, Brazil) 2023To analyze the karyotype test and myeloid panel with next-generation sequencing findings in patients with myelofibrosis, and to compare transplant characteristics in...
OBJECTIVE
To analyze the karyotype test and myeloid panel with next-generation sequencing findings in patients with myelofibrosis, and to compare transplant characteristics in patients referred for bone marrow transplantation.
METHODS
Retrospective, single-center study with patients diagnosed with myelofibrosis treated at Hospital Israelita Albert Einstein between 2010 and 2020.
RESULTS
A total of 104 patients with myelofibrosis were examined. Patients who had not been submitted to tests in our service were excluded. The final sample comprised 69 patients. Of these 69, 56 were submitted to karyotyping and 22 to myeloid panel with next-generation sequencing. Karyotype was normal in 60% of the patients and altered in 40%. The prevalence of high-risk molecular mutations was higher in patients referred for bone marrow transplantation (100% versus 50%). The median follow-up of transplant patients was 2.4 years and the overall survival at 2 years was 80% (95%CI: 62-100%).
CONCLUSION
The molecular analysis enables estimating the patient's risk and thus instituting more aggressive treatment such as bone marrow transplant for patients at higher risk, being a relevant tool to guide therapy. Given the significance of molecular analysis for therapeutic decision-making in myelofibrosis, collection and disclosure of data on the prevalence of cytogenetic changes and findings of next-generation sequencing in affected patients is important.
Topics: Humans; Primary Myelofibrosis; Retrospective Studies; Mutation; Hematopoietic Stem Cell Transplantation; Prognosis
PubMed: 36629680
DOI: 10.31744/einstein_journal/2023AO0100 -
Journal of Bone and Mineral Research :... Apr 2021Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of...
Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss-of-function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b-B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b ) mice. Although male and female Mpig6b mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b mice developed progressive splenomegaly starting at 8 weeks of age. Micro-computed tomography (μCT) of femurs showed that female Mpig6b mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10-week-old female Mpig6b mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b mice also demonstrated improvement in spleen weight compared to sham-operated Mpig6b mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte-driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Bone and Bones; Female; Humans; Male; Megakaryocytes; Mice; Osteosclerosis; Ovariectomy; Primary Myelofibrosis; X-Ray Microtomography
PubMed: 33434328
DOI: 10.1002/jbmr.4245