Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions.
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PMID:Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms. 2302 34

Genome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A. We have recently shown that Dnmt3a is essential for hematopoietic stem cell differentiation. Here, we investigated the effect of loss of Dnmt3a on hematopoietic transformation by forcing the normally quiescent hematopoietic stem cells to divide in vivo. Mice transplanted with Dnmt3a-null bone marrow in the absence of wildtype support cells succumbed to bone marrow failure (median survival, 328 days) characteristic of myelodysplastic syndromes with symptoms including anemia, neutropenia, bone marrow hypercellularity, and splenomegaly with myeloid infiltration. Two out of 25 mice developed myeloid leukemia with >20%blasts in the blood and bone marrow. Four out of 25 primary mice succumbed to myeloproliferative disorders, some of which progressed to secondary leukemia after long latency. Exome sequencing identified cooperating c-Kit mutations found only in the leukemic samples. Ectopic introduction of c-Kit variants into a Dnmt3a-deficient background produced acute leukemia with a short latency (median survival, 67 days). Our data highlight crucial roles of Dnmt3a in normal and malignant hematopoiesis and suggest that a major role for this enzyme is to facilitate developmental progression of progenitor cells at multiple decision checkpoints.
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PMID:Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation. 2561 34

Myeloproliferative neoplasms (MPNs) arise from hematopoietic stem cells (HSCs) with genetic abnormalities in combination with mutations in JAK2, MPL or CALR, which induce autosomal JAK-STAT pathway activation, and mutations in epigenetic regulator genes such as TET2 or DNMT3A. The prognosis of patients with polycythemia vera (PV) or essential thrombocythemia (ET) is relatively good, and the therapeutic goal in cases with PV or ET is to prevent thrombohemorrhagic complications. PV or ET patients at least 60 years of age or with a history of thrombosis are in a high-risk category, and are managed with low dose aspirin and cytoreductive therapy. Phlebotomy to maintain Ht<0.45 is also used to manage PV patients. The median survival for Japanese primary myelofibrosis (MF) patients is 3.9 years. Several factors including age>65 years, Hb<10 g/dl, the presence of constitutional symptoms, and the presence of blasts in blood were identified as being associated with shorter survival in MF patients. Those patients in the high-risk category are candidates for allogenic HSC transplantation (allo-HSCT), which is potentially curative but is also associated with higher therapy-related mortality. High-risk MF patients without indications for allo-HSCT are treated with JAK inhibitors, which can markedly ameliorate constitutional symptoms and splenomegaly, and might thereby lead to a degree of improvement in survival.
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PMID:[Myeloproliferative neoplasms: pathophysiology and therapeutic strategy]. 2645 38

A 75-year-old man with no prior history of cytotoxic therapy presented with increasing fatigue and shortness of breath. He was found to have a new onset of pancytopenia, and chest X-ray showed severe pneumonia. Additional radiology exam revealed pan-lobar pneumonia, pleural effusion, generalized lymphadenopathy and mild splenomegaly. Bone marrow and mediastinal lymph node biopsy from the bilateral level 4 lymph nodes were performed to evaluate the cause of pancytopenia and generalized lymphadenopathy, respectively. Histologic sections of lymph nodes were consistent with angioimmunoblastic T-cell lymphoma (AITL), and bone marrow biopsy showed low level involvement by AITL. Background trilineage hematopoiesis showed features suggestive of myelodysplastic syndrome (MDS) with karyotyping showing deletion 20q; however, interpretation of dysplasia and exclusion of reactive process was difficult due to the presence of severe infection, administration of multiple medications and multiorgan failure. Therefore, to further evaluate the possibility of concomitant myeloid neoplasm, we performed flow cytometry sorting of bone marrow aspirate to isolate the myeloid cell population from the abnormal T-cell population, and comprehensive genomic profiling was performed in each population separately. Flow-sorted myeloid population showed three somatic mutations involving DNMT3A and BCORL1, supporting the diagnosis of MDS in conjunction with the presence of deletion 20q. Flow sorted abnormal T-cell population showed six somatic mutations consistent with AITL, involving Ras homolog gene family member A (RHOA), TET2, DNMT3A, NOTCH2 and XPO1. These two sorted populations shared the DNMT3A p.N612Rfs*26 mutation, and the variants unique to one sorted population were confirmed to be completely absent in another sorted population by manual review of the sample. These findings suggested that the two neoplasms were clonally related and were sharing a common hematopoietic progenitor precursor, but underwent clonal divergence over time, leading to the development of two distinct neoplastic processes of T and myeloid lineages. This illustrates a rare case of concurrent diagnosis of AITL and de novo MDS and reliable genomic assessment was performed at the time of diagnosis to detect mutations in each neoplastic process without contamination. Further studies are needed to assess hypomethylating agents as potential therapy options for these patients.
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PMID:Molecular Genetic Analysis With Flow Cytometry Sorting Identifies Angioimmunoblastic T-Cell Lymphoma and Concomitant De Novo Myelodysplastic Syndrome Arising From the Same Hematopoietic Progenitor. 3322 95