Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of "myeloproliferative disorders (MPD)" by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and "CMPD, unclassifiable." The revised 2008 WHO classification system featured the following changes: 1) the term "CMPD" was replaced by "myeloproliferative neoplasm (MPN)," 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into "CEL not otherwise specified (CEL-NOS)" and "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1"; CEL-NOS remained a subcategory of "MPN," whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies.
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PMID:The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. 1947 96

Hypereosinophilic syndrome (HES) includes heterogeneous hematological disorders that are characterized by distinctive blood and tissue eosinophilia. In addition to classical HES criteria, the World Health Organization proposed a set of criteria that distinguish chronic eosinophilic leukemia (CEL) from HES. As such, the fusion gene FIP1L1/PDGFRA was found as a cause of CEL in a significant proportion of patients initially diagnosed as having HES. Several investigations have tried to dissect the mechanism of leukemogenesis; eosinophilia and signaling induced by FIP1L1/PDGFRalpha in cell lines, bone marrow mast cells, primary human eosinophils and in murine myeloproliferative disorder models. In this review, we introduce the current knowledge on the relationship between FIP1L1/PDGFRalpha and cell signaling, eosinophil proliferation, survival and activation and mastocytosis specially focusing on the evidence learned from murine models.
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PMID:Murine model of hypereosinophilic syndromes/chronic eosinophilic leukemia. 1949 14

The term hypereosinophilic syndrome (HES) was initially introduced to describe a group of diseases all characterized by persistent unexplained hypereosinophilia. Additional names have subsequently been introduced to describe specific variants of HES, such as the myeloid variant and the lymphoid variant, or to indicate idiopathic HES, for which the cause of the eosinophilia is completely unknown. Molecular analysis led to the identification of the clonal origin of several subgroups of HES, clearly establishing these diseases as true leukemias. These cases of hypereosinophilia are now referred to as 'myeloid neoplasms associated with eosinophilia and abnormalities of PDGF receptor A and B (PDGFRA and PDGFRB), or FGF receptor 1 (FGFR1)'. In cases for which clonality is clear, but no PDGFRA, PDGFRB or FGFR1 rearrangement could be demonstrated, the term 'chronic eosinophilic leukemia, not otherwise specified' is preferred. Most importantly, patients with rearrangements of PDGFRA or PDGFRB can be efficiently treated with the kinase inhibitor imatinib. Additional potent kinase inhibitors have been identified, also including inhibitors that target FGFR1 and imatinib-resistant variants of PDGFRalpha. For treatment of unexplained hypereosinophilia and 'chronic eosinophilic leukemia, not otherwise specified; different therapeutic strategies are currently under investigation and promising results have been obtained using humanized anti-IL-5 antibodies. Further molecular understanding of the cause of these 'idiopathic' diseases may lead to the development of novel targeted therapies.
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PMID:Recent breakthroughs in the understanding and management of chronic eosinophilic leukemia. 1976 33

The 2008 WHO classification system for hematological malignancies is comprehensive and includes histology and genetic information. Myeloid neoplasms are now classified into five categories: acute myeloid leukemia, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN, and myeloid and/or lymphoid malignancies associated with eosinophilia and PDGFR or FGFR1 rearrangements. MPN are subclassified into eight separate entities: chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, systemic mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and unclassifiable MPN. The diagnosis of chronic myelogenous leukemia requires the presence of BCR-ABL1, while its absence is required for all other MPN. Additional MPN-associated molecular markers include mutations of JAK2, MPL, TET2 and KIT. JAK2 V617F is found in most patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis and is, therefore, useful as a clonal marker in those settings. The diagnostic utility of MPL and TET2 mutations is limited by low mutational frequency. In systemic mastocytosis, presence of KIT D816V is expected but not essential for diagnosis. Chronic eosinophilic leukemia not otherwise specified should be distinguished from both PDGFR-rearranged or FGFR1-rearranged neoplasms and hypereosinophilic syndrome. We discuss histologic, cytogenetic and molecular changes in MPN and illustrate their integration into practical diagnostic algorithms.
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PMID:Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. 1980 46

The myeloproliferative neoplasms (MPNs) were first recognized by William Dameshek in 1951. The classic MPNs were polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and chronic myelogenous leukemia. They were originally grouped together based on their shared phenotype of myeloproliferation. Since then, important discoveries have been made, identifying a central role of protein tyrosine kinases in the pathogenesis of these disorders. As such, the 2008 WHO diagnostic classification for myeloproliferative neoplasms has incorporated molecular markers with histologic, clinical and laboratory information into the diagnostic algorithms for the MPNs. Important changes include (1) the change of nomenclature of myeloproliferative disorder to myeloproliferative neoplasm emphasizing the clonal nature of these disorders; (2) the classification of mast cell disease as an MPN; (3) the reorganization of the eosinophilic disorders into a molecularly defined category of PDGFRA, PDGFRB and FGFR1-associated myeloid and lymphoid neoplasms with eosinophilia and chronic eosinophilic leukemia, not otherwise specified; and (4) refinement of the diagnostic criteria for PV, ET and PMF incorporating recently described molecular markers, JAK2V617F, JAK2 exon 12 mutations and MPL mutations. This review focuses upon the important changes of the 2008 WHO diagnostic criteria for MPNs.
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PMID:Classification and diagnosis of myeloproliferative neoplasms according to the 2008 World Health Organization criteria. 2019 32

Primary eosinophilic disorders include hypereosinophilic syndrome (HES); chronic eosinophilic leukemia, not otherwise categorized (CEL-NOC); platelet-derived growth factor receptor (PDGFR)-rearranged myeloid neoplasms; and other myeloid malignancies associated with prominent blood eosinophilia. According to the World Health Organization consensus criteria, the diagnosis of HES requires the absence of clonal cytogenetic or molecular markers of an underlying myeloid or lymphoid neoplasm. CEL-NOC constitutes an HES-like phenotype associated with an abnormal karyotype or excess blasts in blood (> 2%) or bone marrow (> 5%). HES and CEL-NOC are considered distinct from molecularly defined eosinophilic disorders, such as those associated with activating mutations of PDGFR (PDGFRA and PDGFRB) and fibroblast growth factor receptor-1. This is an important distinction because PDGFR-mutated but not other eosinophilic neoplasms are effectively treated with imatinib. Current management in HES includes observation only for asymptomatic patients with no evidence of organ damage, systemic corticosteroid therapy for acute control of symptoms, and interferon-alfa-2a or hydroxyurea as steroid-sparing agents. In patients with HES who are refractory to usual therapy and have life-threatening disease complications, the use of investigational drugs such as alemtuzumab or mepolizumab might be considered, but data on long-term efficacy and safety are limited.
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PMID:Primary eosinophilic disorders: a concise review. 2042 45

Since the identification of the FIP1L1/PDGFRA fusion gene as a pathogenic cause of the hypereosinophilic syndrome (HES), the importance of the molecular classification of HES leading to the diagnosis of chronic eosinophilic leukemia (CEL) has been recognized. As a result, a new category, 'myeloid and lymphoid neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB or FGFR1', has recently been added to the new WHO criteria for myeloid neoplasms. FIP1L1/PDGFR alpha-positive disorders are characterized by clonal hypereosinophilia, multiple organ dysfunctions due to eosinophil infiltration, systemic mastocytosis (SM) and a dramatic response to treatment with imatinib mesylate. A murine HES/CEL model by the introduction of FIP1L1/PDGFR alpha and IL-5 overexpression also shows SM, representing patients with FIP1L1/PDGFR alpha-positive HES/CEL/SM. The murine model and the in vitro development system of FIP1L1/PDGFR alpha-positive mast cells revealed the interaction between FIP1L1/PDGFR alpha, IL-5 and stem cell factor in the development of HES/CEL/SM. Current findings of FIP1L1/PDGFR alpha-positive HES/CEL are reviewed focusing on aberrant mast cell development leading to SM.
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PMID:FIP1L1/PDGFR alpha-associated systemic mastocytosis. 2052 72

A 28-year-old man with marked eosinophilia is described. FIP1L1/PDGFRA mRNA showed multiple alternatively-spliced fusion transcripts. Sequencing analysis showed that the deduced DNA breakpoints were intron 10 in the FIP1L1 gene and exon 12 in the PDGFRA gene. Then, a diagnosis of chronic eosinophilic leukemia (CEL) was made. Whereas the response to the treatments with prednisolone and hydroxyurea were unsatisfactory, treatment with imatinib showed a rapid decrease of eosinophils. The hemoglobin level also dropped and bone marrow examination showed pure red cell aplasia. Continued administration of very low dose imatinib (100 mg every 5 days) led to and maintained complete molecular remission, with good tolerability.
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PMID:Pure red cell aplasia associated with imatinib-treated FIP1L1-PDGFRA positive chronic eosinophilic leukemia. 2055 42

Imatinib induces complete molecular response in patients with chronic myeloid leukemia (CML) and chronic eosinophilic leukemia (CEL). However, development of resistance to imatinib has emerged as an important clinical problem for molecular-targeted therapy in CML and CEL. In this study, we have established the imatinib-resistant CEL EOL-1 sub-lines (designated as EOL-1R) by culturing cells with increasing concentrations of imatinib for 6 months. Interestingly, EOL-1R cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene. Exposure of EOL-1R cells to imatinib failed to dephosphorylate AKT, ERK and STAT5, although PDGFRalpha was effectively inactivated. The forced expression of PTEN negatively regulated these signal pathways and sensitized EOL-1R cells to imatinib. Notably, hypermethylation of the promoter region of the PTEN gene in association with the downregulation of this gene's transcripts was identified in imatinib-resistant leukemia cells isolated from individuals with CEL, CML and Philadelphia-positive acute lymphoblastic leukemia. In addition, anti-epigenetic agents restored PTEN expression, resulting in the sensitization of EOL-1R cells to imatinib. Taken together, epigenetic silence of PTEN is one of the mechanisms that cause drug resistance in individuals with leukemia after exposure to imatinib. Anti-epigenetic agents may be useful for overcoming drug resistance in such a case.
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PMID:Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene. 2059 30

We report a rare pediatric chronic eosinophilic leukemia (CEL) case of an 8-year-old male whose leukemic cells carried t(1; 5)(q21; q33) chromosomal abnormality. Sequencing analysis confirmed a TPM3-PDGFRB fusion, and the breakpoint was the same as adult patient. Targeted therapy with imatinib induced a rapid hematologic response and reduction of TPM3-PDGFRB transcripts as monitored by reverse transcription real-time PCR (RT-qPCR). We then established an RT-qPCR assay applicable to detection of all possible PDGFRB fusions and also validated this assay in the patient. These data should provide a valuable reference for management of pediatric CEL.
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PMID:Molecular diagnosis and targeted therapy of a pediatric chronic eosinophilic leukemia patient carrying TPM3-PDGFRB fusion. 2107 21


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