Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary disease process in myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary collagen fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2 tyrosine kinase (V617F) and bcr/abl-negative myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of thrombopoietin (TPOhigh mice) or megakaryocyte lineage restricted underexpression of the transcription factor GATA-1 (GATA-1low mice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived transforming growth factor beta1 in inducing bone marrow fibrosis and stromal cell-derived osteoprotegerin in promoting osteosclerosis. However, experimental myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other cytokines that are implicated in mediating myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and vascular endothelial growth factors. It is currently assumed that such cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived elastase, could also underlie the abnormal peripheral-blood egress of myeloid progenitors in MMM.
...
PMID:Pathogenesis of myelofibrosis with myeloid metaplasia. 1629 80

Myelofibrosis with myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.
...
PMID:International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). 1667 7

Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2(V617)) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2(V617F)-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2(V617F) transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2(V617)) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2(V617F)-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen.
...
PMID:Splenectomy normalizes hematocrit in murine polycythemia vera. 1978 10

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm that involves primarily the megakaryocytic lineage. After many years, a few patients with ET may develop bone marrow (BM) fibrosis and rarely develop osteosclerosis. A 60-yr-old female was admitted due to severe left upper quadrant abdominal discomfort. She had been diagnosed as ET 19 yrs ago. On liver computed tomography severe splenomegaly was shown. Laboratory tests revealed WBC 24.3x10(9)/L, hemoglobin 13.4 g/dL, platelets 432x10(9)/L, lactate dehydrogenase 4,065 IU/L (reference range; 240-480). Blood smear demonstrated leukoerythroblastosis, teardrop cells, and giant and hypogranular platelets. BM study revealed inadequate aspirate due to dry tap. BM biopsy showed clusters of dysplastic megakaryocytes, grade 3 fibrosis, and severe osteosclerosis. Major/minor BCR-ABL1 rearrangement and JAK2 V617F mutation were not detected. Cytogenetic studies revealed normal karyotype. According to the 2008 WHO diagnostic criteria, the patient was diagnosed as having post-essential thrombocythemia myelofibrosis with severe osteosclerosis.
...
PMID:[A case of post-essential thrombocythemia myelofibrosis with severe osteosclerosis]. 2044 28

Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2(Val617F) mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.
...
PMID:Primary myelofibrosis and the "bad seeds in bad soil" concept. 2325 18

A fraction of polycythemia vera (PV) and essential thrombocythemia (ET) cases will, in time, undergo myelofibrotic transformation. In such cases, fibrosis may mask the diagnostic histologic features of the original underlying myeloproliferative neoplasm. Thus, confidently differentiating postfibrotic PV/ET from primary myelofibrosis (PMF) histologically may not be possible. It is controversial whether post-PV/ET myelofibrosis (MF) differs clinicopathologically from PMF, or whether these entities are biologically, clinically, and prognostically indistinguishable. To answer this question, we compared multiple candidate biological, morphologic, and prognostic parameters between 19 postfibrotic ET/PV individuals and 18 PMF individuals. The postfibrotic ET/PV and PMF cases did not differ with regard to clinical outcome, cytogenetic abnormalities, serum lactate dehydrogenase level, peripheral blast count, bone marrow morphology, or grade of reticulin fibrosis. Only JAK2 allele burden, which was higher in the postfibrotic PV/ET population (P=0.011), differed between the 2 groups. Cardinal morphologic features of PMF (ie, marrow cellularity, intrasinusoidal hematopoiesis, osteosclerosis, etc.) were commonly observed in post-PV/ET MF marrow biopsies, and only a minority of post-PV/ET MF marrow biopsies the retained diagnostic features of the primary myeloproliferative neoplasm (panmyelosis in PV and megakaryocytic hyperplasia in ET). Our study indicates that PMF and post-PV/ET MF are clinically and biologically indistinguishable.
...
PMID:Myelofibrotic transformations of polycythemia vera and essential thrombocythemia are morphologically, biologically, and prognostically indistinguishable from primary myelofibrosis. 2489 74

Philadelphia chromosome-negative myeloproliferative neoplasms include primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). Although these 3 entities share many pathogenic characteristics, such as dysregulated Janus kinase (JAK)/signal transducer and activator of transcription signaling, they differ substantially regarding prognosis, progression to myelofibrosis (MF), risk of leukemic transformation, and specific medical needs. Accurate diagnosis and classification of myeloproliferative neoplasms are prerequisites for appropriate risk-based therapy and should be based on an integrated approach following the World Health Organization guidelines that, in addition to clinical, molecular, and cytogenetic evaluation, includes the examination of bone marrow morphology. Reticulin fibrosis at presentation in ET and PV is associated with increased risk of myelofibrotic transformation, and higher fibrosis grade in patients with MF is associated with worse prognosis. Additional assessment of collagen deposition and osteosclerosis may further increase diagnostic and prognostic precision. Moreover, the evaluation of bone marrow pathology has become very important in the new era of disease-modifying agents. In randomized controlled phase 3 studies, the JAK1/JAK2 inhibitor ruxolitinib provided rapid and lasting improvement in MF-related splenomegaly and symptom burden as well as a survival advantage compared with placebo or best available therapy. Follow-up for up to 5 years of patients who participated in a phase 1/2 study of ruxolitinib, revealed stabilization or reversal of bone marrow fibrosis in a proportion of patients with MF. Combinations of JAK inhibitors with other therapies, including agents with antifibrotic and/or anti-inflammatory properties, may possibly decrease bone marrow fibrosis further and favorably influence clinical outcomes.
...
PMID:Impact of bone marrow pathology on the clinical management of Philadelphia chromosome-negative myeloproliferative neoplasms. 2551 54

JAK2 inhibition therapy is used to treat patients suffering from myeloproliferative neoplasms (MPN). Conflicting data on this therapy are reported possibly linked to the types of inhibitors or disease type. Therefore, we decided to compare in mice the effect of a JAK2 inhibitor, Fedratinib, in MPN models of increasing severity: polycythemia vera (PV), post-PV myelofibrosis (PPMF) and rapid post-essential thrombocythemia MF (PTMF). The models were generated through JAK2 activation by the JAK2(V617F) mutation or MPL constant stimulation. JAK2 inhibition induced a correction of splenomegaly, leucocytosis and microcytosis in all three MPN models. However, the effects on fibrosis, osteosclerosis, granulocytosis, erythropoiesis or platelet counts varied according to the disease severity stage. Strikingly, complete blockade of fibrosis and osteosclerosis was observed in the PPMF model, linked to correction of MK hyper/dysplasia, but not in the PTMF model, suggesting that MF development may also become JAK2-independent. Interestingly, we originally found a decreased in the JAK2(V617F) allele burden in progenitor cells from the spleen but not in other cell types. Overall, this study shows that JAK2 inhibition has different effects according to disease phenotypes and can (i) normalize platelet counts, (ii) prevent the development of marrow fibrosis/osteosclerosis at an early stage and (iii) reduce splenomegaly through blockage of stem cell mobilization in the spleen.
...
PMID:JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice. 2617 17

Frameshift mutations in the calreticulin (CALR) gene are seen in about 30% of essential thrombocythemia and myelofibrosis patients. To address the contribution of the CALR mutants to the pathogenesis of myeloproliferative neoplasms, we engrafted lethally irradiated recipient mice with bone marrow cells transduced with retroviruses expressing these mutants. In contrast to wild-type CALR, CALRdel52 (type I) and, to a lesser extent, CALRins5 (type II) induced thrombocytosis due to a megakaryocyte (MK) hyperplasia. Disease was transplantable into secondary recipients. After 6 months, CALRdel52-, in contrast to rare CALRins5-, transduced mice developed a myelofibrosis associated with a splenomegaly and a marked osteosclerosis. Monitoring of virus-transduced populations indicated that CALRdel52 leads to expansion at earlier stages of hematopoiesis than CALRins5. However, both mutants still specifically amplified the MK lineage and platelet production. Moreover, a mutant deleted of the entire exon 9 (CALRdelex9) did not induce a disease, suggesting that the oncogenic property of CALR mutants was related to the new C-terminus peptide. To understand how the CALR mutants target the MK lineage, we used a cell-line model and demonstrated that the CALR mutants, but not CALRdelex9, specifically activate the thrombopoietin (TPO) receptor (MPL) to induce constitutive activation of Janus kinase 2 and signal transducer and activator of transcription 5/3/1. We confirmed in c-mpl- and tpo-deficient mice that expression of Mpl, but not of Tpo, was essential for the CALR mutants to induce thrombocytosis in vivo, although Tpo contributes to disease penetrance. Thus, CALR mutants are sufficient to induce thrombocytosis through MPL activation.
...
PMID:Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. 2696 19

Primary myelofibrosis (PMF), per WHO criteria, is a clonal myeloproliferative neoplasm that usually presents with a proliferation of granulocytic and megakaryocytic lineages with an associated fibrous deposition and extramedullary hematopoiesis. The bone marrow histologic findings of this disorder are typically characterized by the presence of myeloid metaplasia with an associated reactive fibrosis, angiogenesis, and osteosclerosis. However, marked myelofibrosis is not solely confined to PMF and may also be associated with other conditions including but not limited to acute megakaryoblastic leukemias (FAB AML-M7). Here, we describe a rare case of a non-megakaryoblastic acute myeloid leukemia with marked myelofibrosis with osteosclerosis and an isolated trisomy 19. A 19-year-old male presented with severe bone pain of one week duration with a complete blood cell count and peripheral smear showing a mild anemia and occasional circulating blasts. A follow up computed tomography (CT) scan showed diffuse osteosclerosis with no evidence of hepatosplenomegaly or lymphadenopathy. Subsequently, the bone marrow biopsy showed markedly sclerotic bony trabeculae and a hypercellular marrow with marked fibrosis and intervening sheets of immature myeloid cells consistent with myeloblasts with monocytic differentiation. Importantly, these myeloblasts were negative for megakaryocytic markers (CD61 and vWF), erythroid markers (hemoglobin and E-cadherin), and lymphoid markers (CD3, CD19, and TdT). Metaphase cytogenetics showed an isolated triosomy 19 with no JAK2 V617F mutation. The patient was treated with induction chemotherapy followed by allogenic hematopoietic stem cell transplantation which subsequently resulted in a rapid resolution of bone marrow fibrosis, suggesting graft-anti-fibrosis effect. This is a rare case of a non-megakaryoblastic acute myeloid leukemia with myelofibrosis and osteosclerosis with trisomy 19 that may provide insights into the prognosis and therapeutic options of future cases.
...
PMID:Acute Myeloid Leukemia with Isolated Trisomy 19 Associated with Diffuse Myelofibrosis and Osteosclerosis. 2669 66


1 2 Next >>

---