scholarly journals Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel Arthur Corpuz Fisher ◽  
Jared Scott Fowles ◽  
Amy Zhou ◽  
Stephen Tracy Oh
Keyword(s):  
Bone Marrow ◽  
Inflammatory Cytokines ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Failure ◽  
Primary Myelofibrosis ◽  
Extramedullary Hematopoiesis ◽  
Prognostic Indicators ◽  
Bone Marrow Niche ◽  
Nfκb Pathway ◽  
Secondary Myelofibrosis

Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation of polycythemia vera (PV) or essential thrombocythemia (ET) to secondary myelofibrosis (MF), and the equivalent emergence of primary myelofibrosis (PMF). Bone marrow fibrosis itself is thought to be mediated heavily by the cytokine TGF-β, and possibly other cytokines produced as a result of hyperactivated JAK2 kinase in the malignant clone. MF also features extramedullary hematopoiesis and progression to bone marrow failure, both of which may be mediated in part by responses to cytokines. In MF, elevated levels of individual cytokines in plasma are adverse prognostic indicators: elevated IL-8/CXCL8, in particular, predicts risk of transformation of MF to secondary AML (sAML). Tumor necrosis factor (TNF, also known as TNFα), may underlie malignant clonal dominance, based on results from mouse models. Human PV and ET, as well as MF, harbor overproduction of multiple cytokines, above what is observed in normal aging, which can lead to cellular signaling abnormalities separate from those directly mediated by hyperactivated JAK2 or MPL kinases. Evidence that NFκB pathway signaling is frequently hyperactivated in a pan-hematopoietic pattern in MPNs, including in cells outside the malignant clone, emphasizes that MPNs are pan-hematopoietic diseases, which remodel the bone marrow milieu to favor persistence of the malignancy. Clinical evidence that JAK2 inhibition by ruxolitinib in MF neither reliably reduces malignant clonal burden nor eliminates cytokine elevations, suggests targeting cytokine mediated signaling as a therapeutic strategy, which is being pursued in new clinical trials. Greater knowledge of inflammatory pathophysiology in MPNs can therefore contribute to the development of more effective therapy.

scholarly journals TGF-β Signaling in Stromal Cells Contributes to Myelofibrosis, but Not Niche Disruption, in Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1463-1463
Author(s):  
Juo-Chin Yao ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloproliferative Neoplasms ◽  
Extramedullary Hematopoiesis ◽  
Bone Marrow Niche ◽  
Kit Ligand ◽  
Ligand Expression ◽  
The Impact ◽  
Hematopoietic Niche

Abstract Myeloproliferative neoplasms are associated with significant alterations in the bone marrow microenvironment that contribute to disease pathogenesis. The most striking alteration is the development of myelofibrosis, which is characterized by extensive collagen deposition in the bone marrow and is associated with a poor prognosis. Recent evidence suggests that expression of key niche factors, including CXCL12 (stromal derived factor-1, SDF-1) and Kit ligand are reduced in MPNs. This is relevant, since studies by our group and others have shown that deleting these niche factors from stromal cells results in a shift in hematopoiesis from the bone marrow to spleen. Indeed, a prominent feature of MPN is the development of splenomegaly and extramedullary hematopoiesis. There is evidence implicating inflammatory mediators in the development of myelofibrosis. In particular, increased production of TGF-β produced by megakaryocytes and monocytes is found in most patients with MPNs. To assess the role of TGF-β signaling in mesenchymal stromal cells in the bone marrow in the development of myelofibrosis, we generated Osx-Cre; Tgfbr2 f/- mice, in which TGF-β signaling is abrogated in all bone marrow mesenchymal stromal cells (including Lepr + stromal cells), but not endothelial cells or hematopoietic cells. We transplanted MPL W515L transduced hematopoietic stem and progenitor cells (HSPCs) or JAK2 V617F bone marrow into these mice and quantified myelofibrosis using reticulin staining and Collagen 1 and 3 immunostaining. We previously reported that deletion of TGF-β signaling in mesenchymal stromal cells in these mice abrogated the development of myelofibrosis, and we presented evidence that this was mediated by non-canonical JNK-dependent TGF-β signaling. Here, we describe the impact of stromal TGF-β signaling on the bone marrow hematopoietic niche in MPN. MPL W515L transduced HSPCs were transplanted into Osx-Cre; Tgfbr2 f/- mice, and the impact on hematopoietic niche disruption and development of extramedullary hematopoiesis was assessed. In control recipients, transplantation of MPL W515L HSPCs resulted in marked decreases in bone marrow Cxcl12 and Kit ligand expression (Figure 1A-B). Surprisingly, a similar decrease was observed in Osx-Cre; Tgfbr2 f/- recipients. The loss of these key niche factors is predicted to impair hematopoietic niche function in the bone marrow. Consistent with this prediction, total bone marrow cellularity and HSC number were significantly reduced in both control and Osx-Cre; Tgfbr2 f/- recipients (Figure 1C-D). Finally, disruption of the bone marrow niche is often associated with extramedullary hematopoiesis. Indeed, a significant increase in spleen size and spleen HSCs and erythroid progenitors was observed in control recipients (Figure 1E-G). Again, a similar phenotype was observed in Osx-Cre; Tgfbr2 f/- recipients. Collectively, these data show that TGF-β signaling in bone marrow mesenchymal stromal cells is required for the development of myelofibrosis but not hematopoietic niche disruption in MPNs. Thus, these data show for the first time that the signals that induce a fibrogenic program in bone marrow mesenchymal stromal cells are distinct from those that suppress Cxcl12 and Kit ligand expression. Our data show that the fibrogenic program is dependent on non-canonical JNK-dependent TGF-β signaling, while the signals that regulate niche factor expression remain unknown. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cytokine Consistency Between Bone Marrow and Peripheral Blood in Patients With Philadelphia-Negative Myeloproliferative Neoplasms

2021 ◽  
Vol 8 ◽  
Author(s):  
Pu Chen ◽  
Boting Wu ◽  
Lili Ji ◽  
Yanxia Zhan ◽  
Feng Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inflammatory Cytokines ◽  
Peripheral Blood ◽  
Myeloproliferative Neoplasms ◽  
Critical Role ◽  
Primary Myelofibrosis ◽  
Diagnostic Value ◽  
Inflammatory Status ◽  
Bm Niche ◽  
Cytokine Levels

Background: Inflammation might play a critical role in the pathogenesis and progression of Philadelphia-negative myeloproliferative neoplasms (Ph−MPNs) with elevated inflammatory cytokines in peripheral blood (PB). However, the inflammatory status inside the bone marrow (BM), which is the place of malignancy origin and important microenvironment of neoplasm evolution, has not yet been elucidated.Methods: Inflammatory cytokine profiles in PB and BM of 24 Ph-MPNs patients were measured by a multiplex quantitative inflammation array. Cytokines that correlated between PB and BM were selected and then validated by ELISA in a separate cohort of 52 MPN patients. Furthermore, a panel of cytokines was identified and examined for potential application as non-invasive markers for the diagnosis and prediction of fibrosis progress of MPN subtypes.Results: The levels of G-CSF, I-309, IL-1β, IL-1ra, IL-12p40, IL-15, IL-16, M-CSF, MIG, PDGF-BB, and TIMP-1 in BM supernatants were significantly higher than those in PB (all p < 0.05). Linear correlations between BM and PB levels were found in 13 cytokines, including BLC, Eotaxin-2, I-309, sICAM-1, IL-15, M-CSF, MIP-1α, MIP-1δ, RANTES, TIMP-1, TIMP-2, sTNFRI, and sTNFRII (all R > 0.4 and p < 0.05). Levels of BLC, Eotaxin-2, M-CSF, and TIMP-1 in PB were significantly different from those in health controls (all p < 0.05). In PB, levels of TIMP-1 and Eotaxin-2 in essential thrombocythemia (ET) group were significantly lower than those in groups of prefibrotic primary myelofibrosis (pre-PMF) [TIMP-1: 685.2 (322.2–1,229) ng/ml vs. 1,369 (1,175–1,497) ng/ml, p = 0.0221; Eotaxin-2: 531.4 (317.9–756.6) pg/ml vs. 942.4 (699.3–1,474) pg/ml, p = 0.0393] and primary myelofibrosis (PMF) [TIMP-1: 685.2 (322.2–1229) ng/ml vs. 1,365 (1,115–1,681) ng/ml, p = 0.0043; Eotaxin-2: 531.4 (317.9–756.6) pg/ml vs. 1,010 (818–1,556) pg/ml, p = 0.0030]. The level of TIMP-1 in myelofibrosis (MF) >1 group was significantly higher than that in MF ≤ 1 group.Conclusion: Abnormal inflammatory status is present in MPN, especially in its BM microenvironment. Consistency between PB and BM levels was found in multiple inflammatory cytokines. Circulating cytokine levels of BLC, M-CSF, Eotaxin-2, and TIMP-1 reflected inflammation inside BM niche, suggesting potential diagnostic value for MPN subtypes and prognostic value for fibrosis progression.

Myelodysplastic syndromes/myeloproliferative overlap neoplasms

2020 ◽  
pp. 191-203
Author(s):  
Eric Padron ◽  
Tariq I. Mughal ◽  
David Sallman ◽  
Alan F. List
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Failure ◽  
Disease Outcomes ◽  
Genomic Landscape ◽  
Bone Marrow Dysplasia

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are haematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) that display a paradoxical bone marrow phenotype hallmarked by myeloid proliferation in the context of bone marrow dysplasia and ineffective haematopoiesis. The unfolding MDS/MPN genomic landscape has revealed numerous mutations in signalling genes, such as CBL, JAK2, NRAS, KRAS, CSF3R, and others involving the spliceosome complex. These observations suggest that comutation of genes involved in dysplasia and bone marrow failure along with those of cytokine receptor signalling may, in part, explain the dual MDS/MPN phenotype. The respective MDS/MPN diseases are identified by the type of myeloid subset which predominates in the peripheral blood. Currently there are no standard treatment recommendations for most patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic endpoints and standardized response criteria for clinical trials.

Targeting the fibrotic bone marrow niche for treatment of myeloproliferative neoplasms

2016 ◽  
Vol 44 (9) ◽  
pp. S109
Author(s):  
Timothy Campbell ◽  
Si Yi Zhang ◽  
Alexander Valencia ◽  
Emmanuelle Passegue
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Niche

The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy

Blood ◽  
2013 ◽  
Vol 121 (25) ◽  
pp. 5078-5087 ◽  
Author(s):  
Polina Stepensky ◽  
Ann Saada ◽  
Marianne Cowan ◽  
Adi Tabib ◽  
Ute Fischer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Bone Marrow Transplantation ◽  
Bone Marrow Failure ◽  
Primary Myelofibrosis ◽  
Congenital Neutropenia ◽  
Key Points ◽  
New Gene ◽  
Severe Infections ◽  
Intracellular Storage

Key Points VPS45 is a new gene associated with severe infections and bone marrow failure in infancy that can be treated by bone marrow transplantation. The mutation affects intracellular storage and transport and results in increased programmed cell death in neutrophils and bone marrow.

scholarly journals Bone marrow failure and extramedullary hematopoiesis in McCune-Albright syndrome

2017 ◽  
Vol 29 (1) ◽  
pp. 237-241
Author(s):  
C. Robinson ◽  
A. M. Boyce ◽  
A. Estrada ◽  
D. E. Kleiner ◽  
R. Mathew ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Extramedullary Hematopoiesis ◽  
Mccune Albright Syndrome ◽  
Albright Syndrome ◽  
Mccune Albright

Apoptosis and the DNA Damage Response: The Role of the RB Tumor Suppressor Pathway in Oxidative Stress Responses in the Hematopoietic System.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-15-SCI-15
Author(s):  
Kay F. Macleod
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Bone Marrow Failure ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Protein Levels ◽  
Replicative Stress

Abstract Abstract SCI-15 Exposure to pro-oxidants and defects in repair of oxidative base damage is associated with disease and aging and also contributes to the development of anemia, bone marrow failure and hematopoietic malignancies. Our work examines the role of the RB tumor suppressor pathway in the response of the hematopoietic system to oxidative stress and DNA damage. Evidence from mouse models has identified a role for the Rb protein (pRb) in the regulation of hematopoiesis through cell intrinsic functions in blood cell types but also through effects on the bone marrow microenvironment (Spike et al, 2004; Walkley et al, 2007; Daria et al, 2008). Such models have also demonstrated that pRb is required under stress conditions but not under conditions of steady state hematopoiesis (Spike et al, 2004; Spike et al, 2007; Daria et al, 2008). In particular, pRb was required to modulate the response of the hematopoietic system to replicative stress and hypoxia (Spike et al, 2007; Daria et al, 2008). To explain the mechanisms underlying these unique properties of pRb in hematopoiesis, we hypothesized that pRb protein levels are regulated by oxidative stress, including hypoxia and ROS generated as a consequence of stem cell location in the bone marrow niche or in response to replicative stress induced by agents such as 5-fluorouracil. Notably, hypoxia within the bone marrow niche has been reported to promote stem cell expansion and we postulated that this may be due to reduced pRb protein levels in response to hypoxia. We present evidence that pRb protein levels are regulated in wild-type bone marrow in response to replicative stress and that this in turn modulates expansion of stem cells and myeloid progenitors and also impacts end-stage differentiation in the erythroid lineage. Acetylation of pRb stabilized the protein in an active conformation while de-acetylation de-stabilized the protein and promoted pRb protein turnover and increased progenitor cell proliferation. We will present on-going studies that examine how hypoxia and/or ROS affects hematopoietic stem cell proliferation, self-renewal and differentiation in vivo as a function of pRb protein levels using conditional mouse models. The significance of our findings for bone marrow failure in human patients will be discussed. References Spike, B.T. et al. The Rb tumor suppressor is required for stress erythropoiesis. The EMBO J. 2004: 23, 4319-29. Spike, B.T., Dibling, B.C. & Macleod, K.F. Hypoxic stress underlies defects in erythroblast island formation in the Rb null mouse. Blood 2007; 110, 2173-81. Walkley, C.R., Shea, J.M., Sims, N.A., Purton, L.E. & Orkin, S.H. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 2007; 129, 1081-95. Daria, D. et al. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood 2008; 111, 1894-902. Funding: The author is grateful to the J.P. McCarthy Foundation, the Aplastic Anemia and MDS International Foundation and the National Heart Lung & Blood Institute (RO1 HL080262) for funding of work in her laboratory relating to oxidative stress, erythropoiesis and hematopoietic diseases. Disclosures No relevant conflicts of interest to declare.

Regulation of Hematopoietic Stem Cells by Interferons and by DNA Methylation: Implications for Bone Marrow Failure

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-20-SCI-20
Author(s):  
Margaret A. Goodell
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Stem Cell Differentiation ◽  
Primary Myelofibrosis ◽  
Differentiation Potential ◽  
Hematopoietic Stem

Bone marrow failure (BMF), the inability to regenerate the differentiated cells of the blood, has a number of genetic and environmental etiologies, such as mutation of telomere-associated protein genes and immune-related aplastic anemia. Recently, mutations in DNA methyltransferase 3A (DNMT3A) have been found to be associated with approximately 15% of cases of primary myelofibrosis (MF), which can be a cause of BMF. The role of DNMT3A more broadly in hematopoiesis, and specifically in BMF, is currently poorly understood. DNMT3A is one of two de novo DNA methylation enzymes important in developmental fate choice. We showed that Dnmt3a is critical for normal murine hematopoiesis, as hematopoietic stem cells (HSCs) from Dnmt3a knockout (KO) mice displayed greatly diminished differentiation potential while their self-renewal ability was markedly increased1, in effect, leading to failure of blood regeneration or BMF. Combined with loss of Dnmt3b, HSCs exhibited a profound differentiation block, mediated in part by an increase of stabilized b-catenin. While we did not initially observe bone marrow pathology or malignancy development in mice transplanted with Dnmt3a KO HSCs, when we aged a large cohort of mice, all mice succumbed to hematologic disease within about 400 days. Roughly one-third of mice developed frank leukemia (acute lymphocytic leukemia or acute myeloid leukemia), one-third developed MDS, and the remainder developed primary myelofibrosis or chronic myelomonocytic leukemia. The pathological characteristics of the mice broadly mirror those of patients, suggesting the Dnmt3a KO mice can serve as a model for human DNMT3A-mutation associated disease. Strikingly, bone marrow of mice with different disease types exhibit distinct DNA methylation features. These will findings and the implications for disease development will be discussed. We are currently investigating the factors that drive different outcomes in the mice, including stressors such as exposure to interferons. We have hypothesized that HSC proliferation accelerates the Dnnmt3a-associated disease phenotypes. We have previously shown that interferons directly impinge on HSCs in the context of infections. Interferons activate HSCs to divide, generating differentiated progeny and cycling HSCs. Repeated interferon stimulation may permanently impair HSC function and bias stem cell output. When combined with loss of Dnmt3a, interferons may promote BMF. We will discuss broadly how external factors such as aging and infection may collaborate with specific genetic determinants to affect long-term hematopoiesis and malignancy development. Reference: Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 2012; 44: 23-31 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Large Granular Lymphocyte Expansion in Myeloid Diseases and Bone Marrow Failure Syndromes: Whoever Seeks Finds

2021 ◽  
Vol 11 ◽  
Author(s):  
Bruno Fattizzo ◽  
Valentina Bellani ◽  
Raffaella Pasquale ◽  
Juri Alessandro Giannotta ◽  
Wilma Barcellini
Keyword(s):  
Bone Marrow ◽  
Clonal Selection ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Failure ◽  
Pure Red Cell Aplasia ◽  
Lymphoid Cells ◽  
Myeloid Neoplasms ◽  
Bone Marrow Failure Syndromes ◽  
Clonal Origin ◽  
Clinical Conditions

Large granular lymphocytes (LGL) are lymphoid cells characterized by either a T-cell or a natural killer phenotype whose expansion may be reactive to toxic, infectious, and neoplastic conditions, or result from clonal selection. Recently, the higher attention to LGL clones led to their detection in many clinical conditions including myeloid neoplasms and bone marrow failures. In these contexts, it is still unclear whether LGL cells actively contribute to anti-stem cell autoimmunity or are only a reaction to dysplastic/leukemic myelopoiesis. Moreover, some evidence exists about a common clonal origin of LGL and myeloid clones, including the detection of STAT3 mutations, typical of LGL, in myeloid precursors from myelodysplastic patients. In this article we reviewed available literature regarding the association of LGL clones with myeloid neoplasms (myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemias) and bone marrow failures (aplastic anemia and pure red cell aplasia, PRCA) focusing on evidence of pathogenic, clinical, and prognostic relevance. It emerged that LGL clones may be found in up to one third of patients, particularly those with PRCA, and are associated with a more cytopenic phenotype and good response to immunosuppression. Pathogenically, LGL clones seem to expand after myeloid therapies, whilst immunosuppression leading to LGL depletion may favor leukemic escape and thus requires caution.

scholarly journals MPL W515 L/K mutations in myeloproliferative neoplasms

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sohaila Eldeweny ◽  
Hosny Ibrahim ◽  
Ghada Elsayed ◽  
Mohamed Samra
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Ethnic Groups ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Myelogenous Leukemia ◽  
Egyptian Population ◽  
Ph Chromosome ◽  
Pathological Variant

Abstract Background Myeloproliferative neoplasms (MPNs) describe a group of diseases involving the bone marrow (BM). Classical MPNs are classified into chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This classification is based on the presence of Philadelphia (Ph) chromosome (BCR/ABL1). CML is BCR/ABL1-positive while PV, ET, and PMF are negative. JAK2 p. Val617Phe pathological variant is the most associated mutation in BCR/ABL1-negative MPNs. The frequency of JAK2 p. Val617Phe is 90–95% in PV patients, 50–60% in ET, and 40–50% in patients with PMF. Studies on MPL gene led to the revelation of a gain of function pathological variants in JAK2 p. Val617Phe-negative myeloproliferative neoplasms (MPNs). MPL p. W515 L/K pathological variants are the most common across all mutations in MPL gene. The prevalence of these pathological variants over the Egyptian population is not clear enough. In the present study, we aimed to investigate the prevalence of MPL p. W515 L/K pathological variants in the Philadelphia (Ph)-negative MPNs over the Egyptian population. Results We have tested 60 patients with Ph-negative MPNs for MPL p. W515 L/K pathological variants. Median age was 51 (22–73) years. No MPL p. W515 L/K pathological variants were detected among our patients. JAK2 p. Val617Phe in PV and PMF patients showed significantly lower frequency than other studies. Splenomegaly was significantly higher in ET patients compared to other studies. Conclusion MPL p. W515 L/K pathological variants are rare across the Egyptian Ph-negative MPNs, and further studies on a large number are recommended. MPN patients in Egypt are younger compared to different ethnic groups.

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