Increased prevalence of autoimmune phenomena in myelofibrosis: Relationship with clinical and morphological characteristics, and with immunoregulatory cytokine patterns

Barcellini, Wilma; Iurlo, Alessandra; Radice, Tommaso; Imperiali, Francesca Guia; Zaninoni, Anna; Fattizzo, Bruno; Guidotti, Francesca; Bianchi, Paola; Fermo, Elisa; Consonni, Dario; Cortelezzi, Agostino

doi:10.1016/j.leukres.2013.09.001

Cited by 33 publications

(32 citation statements)

References 47 publications

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“…This hypothesis was tested by demonstrating that the plasma of PMF patients contains levels of mDNA and AMA greater than normal. These results confirm a previous hypothesis for the presence of autoimmune dysfunction in PMF 36 based on reports indicating that plasma of PMF patients contains antibodies against red cells and platelets 37 and that the risk to develop myeloproliferative neoplasms is significantly increased by a prior history of autoimmune diseases 38 .…”

Section: Discussionsupporting

confidence: 91%

Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

Ciaffoni

Cassella

Varricchio

et al. 2015

Blood Cells, Molecules, and Diseases

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Primary myelofibrosis (PMF) is characterized by megakaryocyte hyperplasia, dysplasia and death with progressive reticulin/collagen fibrosis in marrow and hematopoiesis in extramedullary sites. The mechanism of fibrosis was investigated by comparing TGF-β1 signaling of marrow and spleen of patients with PMF and of non-diseased individuals. Expression of 39 (23 up-regulated and 16 down-regulated) and 38 (8 up-regulated and 30 down-regulated) TGF-β1 signaling genes was altered in marrow and spleen of PMF patients, respectively. Abnormalities included genes of TGF-β1 signaling, cell cycling and abnormal in chronic myeloid leukemia (EVI1 and p21CIP) (both marrow and spleen) and Hedgehog (marrow only) and p53 (spleen only) signaling. Pathway analyses of these alterations predict increased osteoblast differentiation, ineffective hematopoiesis and fibrosis driven by non-canonical TGF-β1 signaling in marrow and increased proliferation and defective DNA repair in spleen. Since activation of non-canonical TGF-β1 signaling is associated with fibrosis in autoimmune diseases, the hypothesis that fibrosis in PMF results from an autoimmune process triggered by dead megakaryocytes was tested by determining that PMF patients expressed plasma levels of mitochondrial DNA and anti-mitochondrial antibodies greater than normal controls. These data identify autoimmunity as a possible cause of marrow fibrosis in PMF.

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Section: Discussionsupporting

confidence: 91%

Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

Ciaffoni

Cassella

Varricchio

et al. 2015

Blood Cells, Molecules, and Diseases

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“…Autoimmune phenomena and cytokine dysregulation also appear to play an important role in MPN-associated myelofibrosis [33]. In addition, patients with autoimmune diseases are at a modestly higher risk of developing MPNs [34], and approximately 80% of patients with PMF, postessential thrombocythemia myelofibrosis, and postpolycythemia vera myelofibrosis have detectable autoantibodies [26].…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Myelofibrosis: Clinical Features, Course, and Outcome

Piatek¹,

Vergara‐Lluri

Pullarkat

et al. 2017

Acta Haematol

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Background: Autoimmune myelofibrosis (AIMF) is an underrecognized cause of nonmalignant bone marrow fibrosis which occurs in the presence or absence of a defined systemic autoimmune disease. Patients with AIMF present with cytopenias and autoantibodies, and have a distinctive nonclonal myelofibrosis on bone marrow examination. AIMF is distinguished from primary myelofibrosis by the absence of splenomegaly, eosinophilia, or basophilia, and the absence of abnormal myeloid, erythroid, or megakaryocytic morphology. Objectives: The objective of the study was to describe the clinical presentation and outcomes of patients with AIMF. Methods: We conducted a single-institution, retrospective chart review of patients diagnosed with AIMF to investigate clinical presentations, therapies, and outcomes. Results: Twelve patients with AIMF were identified with a mean follow-up of 5.8 years. All patients had detectable autoantibodies and the majority had concomitant autoimmune disorders. Four patients experienced a complete response of cytopenias and 3 patients experienced a partial response (PR) of cytopenias with immunosuppressive therapy. One patient achieved a PR following splenectomy. No patients were diagnosed with myeloproliferative neoplasms during the follow-up period. Conclusions: AIMF contributes to cytopenias in the subset of patients with various autoimmune disorders. The majority of patients with AIMF experience an improvement in cytopenias with immunosuppressive therapy.

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“…The underlying reasons are most likely pleotropic and may include autoimmune-driven tumorigenesis, therapeutic-related effects, or even shared host or environmental susceptibilities. Furthermore, Barcellini et al analysed 100 MF patients and found a high incidence of organ-specific and non-organ-specific autoantibodies, most likely reflecting the inherent deregulated immune milieu [39].…”

Section: Mpn-associated Inflammation and Immune Deregulation: What Domentioning

confidence: 99%

Immunological Consequences of JAK Inhibition: Friend or Foe?

McLornan

Khan

Harrison

2015

Curr Hematol Malig Rep

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Over the last decade, unparalleled advances have been made within the field of 'Philadelphia chromosome'-negative myeloproliferative neoplasms (MPN) regarding both disease pathogenesis and therapeutic targeting. The discovery of deregulated JAK-STAT signalling in MPN led to the rapid development of JAK inhibitor agents, targeting both mutated and wild-type JAK, which have significantly altered the therapeutic paradigm for patients with MPN. Although the largest population treated with these agents incorporates those with myelofibrosis, increasing data supports potential usage in other MPNs such as essential thromocythaemia and polycythaemia vera. Many MPNs are associated with a hyperinflammatory state and deregulation of immune homeostasis. Over the last few years, research has focused on attempting to decipher the complex and context-dependent changes that contribute to this immune deregulation. Moreover, very recent studies have demonstrated significant JAK inhibitor-mediated effects within the T cell, natural killer cell and dendritic cell compartments following exposure to JAK inhibitors. In parallel, case reports of infections occurring following exposure to ruxolitinib, many of which are atypical, have focused research efforts on delineating JAK inhibitor-associated immunological consequences. Within this review article, we will describe what is currently known about MPN-associated immune deregulation and JAK inhibitor-mediated immunomodulation.

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Increased prevalence of autoimmune phenomena in myelofibrosis: Relationship with clinical and morphological characteristics, and with immunoregulatory cytokine patterns

Cited by 33 publications

References 47 publications

Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

Activation of non-canonical TGF-β1 signaling indicates an autoimmune mechanism for bone marrow fibrosis in primary myelofibrosis

Autoimmune Myelofibrosis: Clinical Features, Course, and Outcome

Immunological Consequences of JAK Inhibition: Friend or Foe?

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