-
Nature Communications Sep 2022Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including...
Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1β serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1β overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1β in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1β in JAK2-V617F mutant mice by anti-IL-1β antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1β with anti-IL-1β antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.
Topics: Animals; Interleukin-1beta; Janus Kinase 2; Mice; Mice, Knockout; Myeloproliferative Disorders; Neoplasms; Nitriles; Osteosclerosis; Primary Myelofibrosis; Pyrazoles; Pyrimidines
PubMed: 36100613
DOI: 10.1038/s41467-022-32927-4 -
The Korean Journal of Internal Medicine Jul 2018Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) in which dysregulation of the Janus kinase/signal transducers and activators of transcription... (Review)
Review
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) in which dysregulation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways is the major pathogenic mechanism. Most patients with PMF carry a driver mutation in the JAK2, MPL (myeloproliferative leukemia), or CALR (calreticulin) genes. Mutations in epigenetic regulators and RNA splicing genes may also occur, and play critical roles in PMF disease progression. Based on revised World Health Organization diagnostic criteria for MPNs, both screening for driver mutations and bone marrow biopsy are required for a specific diagnosis. Clinical trials of JAK2 inhibitors for PMF have revealed significant efficacy for improving splenomegaly and constitutional symptoms. However, the currently available drug therapies for PMF do not improve survival. Although allogeneic stem cell transplantation is potentially curative, it is associated with substantial treatment-related morbidity and mortality. PMF is a heterogeneous disorder and decisions regarding treatments are often complicated, necessitating the use of prognostic models to determine the management of treatments for individual patients. This review focuses on the clinical aspects and outcomes of a cohort of Japanese patients with PMF, including discussion of recent advances in the management of PMF.
Topics: Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Primary Myelofibrosis; Protein Kinase Inhibitors; Splenomegaly
PubMed: 29665657
DOI: 10.3904/kjim.2018.033 -
Archives of Pathology & Laboratory... Oct 2016Evaluation of peripheral blood and bone marrow for an indication of persistent eosinophilia can be a challenging task because there are many causes of eosinophilia and... (Review)
Review
Evaluation of peripheral blood and bone marrow for an indication of persistent eosinophilia can be a challenging task because there are many causes of eosinophilia and the morphologic differences between reactive and neoplastic causes are often subtle or lack specificity. The purpose of this review is to provide an overview of the differential diagnosis for eosinophilia, to recommend specific steps for the pathologist evaluating blood and bone marrow, and to emphasize 2 important causes of eosinophilia that require specific ancillary tests for diagnosis: myeloproliferative neoplasm with PDGFRA rearrangement and lymphocyte-variant hypereosinophilic syndrome.
Topics: Bone Marrow; Diagnosis, Differential; Eosinophilia; Gene Rearrangement; Humans; Hypereosinophilic Syndrome; Myeloproliferative Disorders; Oncogene Proteins, Fusion; Prognosis; Receptor, Platelet-Derived Growth Factor alpha
PubMed: 27684977
DOI: 10.5858/arpa.2016-0223-RA -
Cancer Research Communications May 2023Interferons (IFNs) are cytokines with potent antineoplastic and antiviral properties. IFNα has significant clinical activity in the treatment of myeloproliferative...
UNLABELLED
Interferons (IFNs) are cytokines with potent antineoplastic and antiviral properties. IFNα has significant clinical activity in the treatment of myeloproliferative neoplasms (MPN), but the precise mechanisms by which it acts are not well understood. Here, we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B), an Unc-51-like kinase 1 (ULK1)-interactive protein in the nuclear compartment of malignant cells, is overexpressed in patients with MPN. Remarkably, targeted silencing of enhances transcription of IFNα-stimulated genes and promotes IFNα-dependent antineoplastic responses in primary MPN progenitor cells. Taken together, our findings indicate that CHAF1B is a promising newly identified therapeutic target in MPN and that CHAF1B inhibition in combination with IFNα therapy might offer a novel strategy for treating patients with MPN.
SIGNIFICANCE
Our findings raise the potential for clinical development of drugs targeting CHAF1B to enhance IFN antitumor responses in the treatment of patients with MPN and should have important clinical translational implications for the treatment of MPN and possibly in other malignancies.
Topics: Humans; Myeloproliferative Disorders; Bone Marrow Neoplasms; Interferon-alpha; Neoplasms; Chromatin Assembly Factor-1
PubMed: 37377894
DOI: 10.1158/2767-9764.CRC-23-0010 -
Advances in Therapy May 2020Patients with myeloproliferative neoplasms (MPNs), a group of rare haematological conditions including polycythaemia vera, essential thrombocythaemia, and myelofibrosis,... (Review)
Review
Patients with myeloproliferative neoplasms (MPNs), a group of rare haematological conditions including polycythaemia vera, essential thrombocythaemia, and myelofibrosis, often experience a range of symptoms which can significantly impact their quality of life (QoL). Although symptom burden is highest in myelofibrosis and high-risk patients, lower-risk patients also report symptoms impacting their daily life and ability to work. In addition to physical symptoms, MPNs affect emotional well-being, with anxiety and depression frequently reported by patients. Despite significant advances in treatment options, such as the introduction of JAK1/JAK2 inhibitors, therapy for MPNs is often palliative; therefore, reduction of symptoms and improvement of QoL should be considered as major treatment goals. One of the main issues impacting MPN treatment is the discord between patient and physician perceptions of symptom burden, treatment goals, and expectations. New technologies, such as app-based reporting, can aid this communication, but are still not widely implemented. Additionally, regional variation further affects the psychosocial burden of MPNs on patients and their associates, as treatments and access to clinical trials are options for patients living in some areas, but not others. Overcoming some of the challenges in patient-physician communication and treatment access are key to improving disease management and QoL, as well as giving the patient greater input in treatment decisions.
Topics: Antineoplastic Agents; Disease Management; Female; Hematologic Neoplasms; Humans; Janus Kinase 1; Janus Kinase 2; Male; Myeloproliferative Disorders; Physician-Patient Relations; Protein Kinase Inhibitors; Quality of Life; Severity of Illness Index
PubMed: 32329011
DOI: 10.1007/s12325-020-01314-0 -
Experimental Hematology Aug 2015Major progress has been recently made in understanding the molecular pathogenesis of myeloproliferative neoplasms (MPN). Mutations in one of four genes-JAK2, MPL, CALR,... (Review)
Review
Major progress has been recently made in understanding the molecular pathogenesis of myeloproliferative neoplasms (MPN). Mutations in one of four genes-JAK2, MPL, CALR, and CSF3R-can be found in the vast majority of patients with MPN and represent driver mutations that can induce the MPN phenotype. Hyperactive JAK/STAT signaling appears to be the common denominator of MPN, even in patients with CALR mutations and the so-called "triple-negative" MPN, where the driver gene mutation is still unknown. Mutations in epigenetic regulators, transcription factors, and signaling components modify the course of the disease and can contribute to disease initiation and/or progression. The central role of JAK2 in MPN allowed development of small molecular inhibitors that are in clinical use and are active in almost all patients with MPN. Advances in understanding the mechanism of JAK2 activation open new perspectives of developing the next generation of inhibitors that will be selective for the mutated forms of JAK2.
Topics: Animals; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Humans; Mutation; Myeloproliferative Disorders; Neoplasm Proteins; Signal Transduction
PubMed: 26209551
DOI: 10.1016/j.exphem.2015.06.007 -
Frontiers in Immunology 2020The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and... (Review)
Review
The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and transformation to acute myeloid leukemia (AML). JAK2 inhibitors improve the quality of life for MPN patients, but these approved therapeutics do not readily reduce the natural course of disease or antagonize the neoplastic clone. An understanding of the molecular and cellular changes requisite for MPN development and progression are needed to develop improved therapies. Recently, murine MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on glucose. Neoplastic hematopoietic progenitor cells in these mice express elevated levels of glycolytic enzymes and exhibit enhanced levels of glycolysis and oxidative phosphorylation, and the disease phenotype of these MPN model mice is antagonized by glycolytic inhibition. While all MPN-driving mutations lead to aberrant JAK2 activation, these mutations often co-exist with mutations in genes that encode epigenetic regulators, including loss of function mutations known to enhance MPN progression. In this perspective we discuss how altered activity of epigenetic regulators (e.g., methylation and acetylation) in MPN-driving stem and progenitor cells may alter cellular metabolism and contribute to the MPN phenotype and progression of disease. Specific metabolic changes associated with epigenetic deregulation may identify patient populations that exhibit specific metabolic vulnerabilities that are absent in normal hematopoietic cells, and thus provide a potential basis for the development of more effective personalized therapeutic approaches.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Janus Kinase 2; Janus Kinase Inhibitors; Molecular Targeted Therapy; Mutation; Myeloproliferative Disorders; Neoplasms; Neoplastic Stem Cells; Phenotype
PubMed: 33329600
DOI: 10.3389/fimmu.2020.604142 -
Experimental Hematology Mar 2020Recent advances in DNA sequencing technologies have enhanced our knowledge about several diseases. Coupled with easy accessibility to blood samples, hematology plays a... (Review)
Review
Recent advances in DNA sequencing technologies have enhanced our knowledge about several diseases. Coupled with easy accessibility to blood samples, hematology plays a leading role in understanding the process of carcinogenesis. Clonal hematopoiesis (CH) with somatic mutations is observed in at least 10% of people over 65 years of age, without apparent hematologic disorders. CH is associated with increased risk of hematologic malignancies, which is indicative of a pre-malignant condition. Therefore, a better understanding of CH will help elucidate the mechanism of multi-step tumorigenesis in the hematopoietic system. Somatic mutations of ASXL1 are frequently detected in CH and myeloid malignancies. Although ASXL1 does not have any catalytic activity, it is involved in multiple histone modifications including H3K4me3, H3K27me3, and H2AK119Ub, suggesting its function as a scaffolding protein. Most ASXL1 mutations detected in CH and myeloid malignancies are frameshift or nonsense mutations of the last exon, generating a C-terminally truncated protein. Deletion of Asxl1 or expression of mutant ASXL1 in mice alters histone modifications and facilitates aberrant gene expression, resulting in myeloid transformation. On the contrary, these mice exhibit impaired functioning of hematopoietic stem cells (HSCs), suggesting the negative effects of ASXL1 mutations on stem cell function. Thus, how ASXL1 mutations induce a clonal advantage of hematopoietic cells and subsequent CH development has not been elucidated. Here, we have reviewed the current literature that enhances our understanding of ASXL1, including its mutational landscape, function, and involvement of its mutation in pathogenesis of CH and myeloid malignancies. Finally, we discuss the potential causes of CH harboring ASXL1 mutations with our latest knowledge.
Topics: Aged; Aging; Animals; Clonal Evolution; Codon, Nonsense; Hematologic Neoplasms; Hematopoiesis; Humans; Myeloproliferative Disorders; Neoplasm Proteins; Repressor Proteins
PubMed: 31945396
DOI: 10.1016/j.exphem.2020.01.002 -
Haematologica Jan 2017The myeloproliferative neoplasms are a heterogeneous group of clonal disorders characterized by the overproduction of mature cells in the peripheral blood, together with... (Review)
Review
The myeloproliferative neoplasms are a heterogeneous group of clonal disorders characterized by the overproduction of mature cells in the peripheral blood, together with an increased risk of thrombosis and progression to acute myeloid leukemia. The majority of patients with Philadelphia-chromosome negative myeloproliferative neoplasms harbor somatic mutations in Janus kinase 2, leading to constitutive activation. Acquired mutations in calreticulin or myeloproliferative leukemia virus oncogene are found in a significant number of patients with essential thrombocythemia or myelofibrosis, and mutations in numerous epigenetic regulators and spliceosome components are also seen. Although the cellular and molecular consequences of many of these mutations remain unclear, it seems likely that they interact with germline and microenvironmental factors to influence disease pathogenesis. This review will focus on the determinants of specific myeloproliferative neoplasm phenotypes as well as on how an improved understanding of molecular mechanisms can inform our understanding of the disease entities themselves.
Topics: Animals; Biomarkers; Disease Susceptibility; Environment; Gene Expression Regulation; Humans; Mutation; Myeloproliferative Disorders; Phenotype; Receptors, Cytokine; Signal Transduction
PubMed: 27909216
DOI: 10.3324/haematol.2014.113845 -
British Journal of Haematology Oct 2018The 2016 World Health Organization (WHO) classification for myeloproliferative neoplasms (MPN) divided myelofibrosis (MF) into pre-fibrotic (pre-MF) and overt-MF... (Review)
Review
The 2016 World Health Organization (WHO) classification for myeloproliferative neoplasms (MPN) divided myelofibrosis (MF) into pre-fibrotic (pre-MF) and overt-MF categories. This new classification, particularly the entity pre-MF, has been a subject of discussion between experts. Important questions have been raised in recent years, such as the need for bone marrow trephine for diagnosis; how this is interpreted and the weighting given to it in assigning a diagnosis; determination of prognosis for pre-MF patients; including which scoring system to use and, ultimately, an evidence-based management plan for this group of patients. Many pre-MF patients present as young adults, with thrombocytosis, elevated lactate dehydrogenase levels and increased bone marrow fibrosis (i.e. ≥ grade 1). Current management strategies differ in view of age, comorbidities and bone marrow features and the opinion of the managing clinicians. Prognostic scoring systems have some limitations regarding this entity, and at the present time there is limited information about the overall survival and incidence of progression to overt-MF and acute leukaemia for pre-MF. In this clinically focussed article, we review the main characteristics of this new disease category in view of the current published literature and illustrate our discussion with some real patient cases. Lastly, we propose a management strategy for patients to whom this diagnostic label is applied.
Topics: Disease Management; Fibrosis; Humans; Myeloproliferative Disorders; Primary Myelofibrosis; Prognosis; World Health Organization
PubMed: 30328618
DOI: 10.1111/bjh.15562