scholarly journals Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR–ABL-Negative Myeloproliferative Neoplasm

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1037
Author(s):  
Alessandro Allegra ◽  
Giovanni Pioggia ◽  
Alessandro Tonacci ◽  
Marco Casciaro ◽  
Caterina Musolino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Chronic Inflammation ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Tumor Stage ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms ◽  
Inflammatory State

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In BCR–ABL1-negative MPNs, the driver mutations include JAK 2, MPL, and CALR. Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.

scholarly journals The Thrombopoietin Receptor, MPL, Is a Therapeutic Target of Opportunity in the MPN

2021 ◽  
Vol 11 ◽  
Author(s):  
Jerry L. Spivak ◽  
Alison R. Moliterno
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Therapeutic Target ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Thrombopoietin Receptor

The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis share driver mutations that either activate the thrombopoietin receptor, MPL, or indirectly activate it through mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, although the myeloproliferative neoplasms are classified as neoplasms because they are clonal hematopoietic stem cell disorders, the mutations affecting MPL or JAK2 are gain-of-function, resulting in increased production of normal erythrocytes, myeloid cells and platelets. Constitutive JAK2 activation provides the basis for the shared clinical features of the myeloproliferative neoplasms. A second molecular abnormality, impaired posttranslational processing of MPL is also shared by these disorders but has not received the recognition it deserves. This abnormality is important because MPL is the only hematopoietic growth factor receptor expressed in hematopoietic stem cells; because MPL is a proto-oncogene; because impaired MPL processing results in chronic elevation of plasma thrombopoietin, and since these diseases involve normal hematopoietic stem cells, they have proven resistant to therapies used in other myeloid neoplasms. We hypothesize that MPL offers a selective therapeutic target in the myeloproliferative neoplasms since impaired MPL processing is unique to the involved stem cells, while MPL is required for hematopoietic stem cell survival and quiescent in their bone marrow niches. In this review, we will discuss myeloproliferative neoplasm hematopoietic stem cell pathophysiology in the context of the behavior of MPL and its ligand thrombopoietin and the ability of thrombopoietin gene deletion to abrogate the disease phenotype in vivo in a JAK2 V617 transgenic mouse model of PV.

Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

2021 ◽  
Vol 41 (03) ◽  
pp. 197-205
Author(s):  
Franziska C. Zeeh ◽  
Sara C. Meyer
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Mutational Analysis ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Standard Of Care ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Therapeutic Decisions ◽  
Jak2 Inhibitors

AbstractPhiladelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

scholarly journals JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F–positive essential thrombocythemia

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1528-1538 ◽  
Author(s):  
Juan Li ◽  
Dominik Spensberger ◽  
Jong Sook Ahn ◽  
Shubha Anand ◽  
Philip A. Beer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Essential Thrombocythemia ◽  
Cell Function ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Transgenic Models ◽  
Disease Phenotype ◽  
Hematopoietic Stem

The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F–positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2V617F mice develop reduced numbers of lineage−Sca-1+c-Kit+ cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.

scholarly journals Combination approach to diagnosis and treatment of an elderly patient with chronic Ph-negative myeloproliferative neoplasm and concomitant surgical pathology. Clinical observation

MD-Onco ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 61-65
Author(s):  
Yu. E. Ryabukhina ◽  
P. A. Zeynalova ◽  
O. I. Timofeeva ◽  
F. M. Abbasbeyli ◽  
T. V. Ponomarev ◽  
...  
Keyword(s):  
Elderly Patient ◽  
Essential Thrombocythemia ◽  
Early Stage ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Left Femur ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.

scholarly journals The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 113
Author(s):  
Elena Genovese ◽  
Margherita Mirabile ◽  
Sebastiano Rontauroli ◽  
Stefano Sartini ◽  
Sebastian Fantini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Oxidative Dna Damage ◽  
Myeloproliferative Neoplasm ◽  
High Plasma ◽  
Driver Mutations ◽  
Poor Overall Survival ◽  
Jak2 Mutation ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidant capacity (TAC) correlate with detrimental clinical features, such as high levels of lactate dehydrogenase (LDH) and circulating CD34+ cells. Moreover, in JAK2-mutated patients, high plasma level of TAC is also associated with a poor overall survival (OS), and multivariate analysis demonstrated that high TAC classification is an independent prognostic factor allowing the identification of patients with inferior OS in both DIPSS lowest and highest categories. Altogether, our data suggest that a different capability to respond to oxidative stress can be one of the mechanisms underlying disease progression of myelofibrosis.

scholarly journals Cell competition between wild-type and JAK2V617F mutant cells in a murine model of a myeloproliferative neoplasm

2020 ◽  
Author(s):  
Melissa Castiglione ◽  
Haotian Zhang ◽  
Huichun Zhan
Keyword(s):  
Stem Cell ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
List Type ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Mutant Cells

AbstractThe myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by overproduction of mature blood cells and increased risk of transformation to frank leukemia. The acquired kinase mutation JAK2V617F plays a central role in a majority of these disorders. The hematopoietic stem cell (HSC) compartment in MPN is heterogeneous with the presence of both JAK2 wild-type and JAK2V617F mutant cells in most patients with MPN. Utilizing in vitro co-culture assays and in vivo competitive transplantation assays, we found that the presence of wild-type cells altered the behavior of co-existing JAK2V617F mutant cells, and a mutant microenvironment (niche) could overcome the competition between wild-type and mutant cells, leading to mutant clonal expansion and overt MPN. We also demonstrated that competition between wild-type and JAK2V617F mutant cells triggered a significant immune response, and there was a dynamic PD-L1 deregulation in the mutant stem/progenitor cells caused by their interactions with the neighboring wild-type cells and the microenvironment. Therefore, while accumulation of oncogenic mutations is unavoidable during aging, our data suggest that, if we could therapeutically enhance normal cells’ ability to compete, we might be better able to control neoplastic cell expansion and prevent the development of a full-blown malignancy.Key PointsThe presence of wild-type cells alters the behavior of co-existing JAK2V617F mutant cellsA mutant microenvironment overcomes the competition between wild-type and JAK2V617F mutant cells, leading to the development of a MPN

scholarly journals Cancer Immune Therapy for Philadelphia Chromosome-Negative Chronic Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1763 ◽  
Author(s):  
Morten Orebo Holmström ◽  
Hans Carl Hasselbalch ◽  
Mads Hald Andersen
Keyword(s):  
Cancer Immunotherapy ◽  
Myeloproliferative Neoplasms ◽  
Immune Therapy ◽  
Philadelphia Chromosome ◽  
Driver Mutations ◽  
Interferon Α ◽  
Therapeutic Vaccination ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms ◽  
Anti Cancer

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN.

scholarly journals Bone marrow–specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (19) ◽  
pp. 2053-2066 ◽  
Author(s):  
Anna Chorzalska ◽  
John Morgan ◽  
Nagib Ahsan ◽  
Diana O. Treaba ◽  
Adam J. Olszewski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Marrow Transplant ◽  
Negative Regulator ◽  
Hematopoietic Stem ◽  
Regulatory Module ◽  
Signaling Axis

Abstract Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of Abi1 in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF. Abi1 loss resulted in a significant increase in the activity of the Src family kinases (SFKs), STAT3, and NF-κB signaling. We also observed impairment of hematopoietic stem cell self-renewal and fitness, as evidenced in noncompetitive and competitive bone marrow transplant experiments. CD34+ hematopoietic progenitors and granulocytes from patients with PMF showed decreased levels of ABI1 transcript as well as increased activity of SFKs, STAT3, and NF-κB. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/STAT3/NF-κB signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF.

scholarly journals VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms

2021 ◽  
Vol 22 (13) ◽  
pp. 6671
Author(s):  
Tijana Subotički ◽  
Olivera Mitrović Ajtić ◽  
Emilija Živković ◽  
Miloš Diklić ◽  
Dragoslava Đikić ◽  
...  
Keyword(s):  
Protein Expression ◽  
Chronic Inflammation ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Angiogenic Factors ◽  
Mtor Signaling ◽  
Angiogenic Factor ◽  
Inflammatory Signaling ◽  
Gene And Protein Expression ◽  
Hel Cells

Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.

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