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

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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)

Hepatocyte growth factor (HGF) and its receptor MET are essential during embryonic development and throughout postnatal life. However, aberrant MET activation, due to overexpression, mutations, or autocrine ligand production, contributes to the development and progression of a variety of human cancers, often being associated with poor clinical outcome and drug resistance. B cell malignancies arise from B cells that are clonally expanded at different stages of differentiation. Despite major therapeutic advances, most mature B cell malignancies remain incurable and biologically-oriented therapeutic strategies are urgently needed. This review addresses the role of the HGF/MET pathway during B cell development and discusses how its aberrant activation contributes to the development of B cell lymphoproliferative disorders, with particular emphasis on multiple myeloma and diffuse large B cell lymphoma. These insights, combined with the recent development of clinical-grade agents targeting the MET pathway, provide the rationale to envision the HGF/MET pathway as a new promising target for the treatment of B cell malignancies.
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PMID:The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas. 2065 87

Anaplastic large cell lymphoma (ALCL) accounts for 10% to 30% of all childhood lymphomas and approximately 5% of all non-Hodgkin's lymphoma. ALCL is considered to be a T-cell non-Hodgkin's lymphoma that can be divided into two major groups with distinct genetic, immunophenotypic, and clinical behaviors. The first group consists of a spectrum of CD30+ T-cell lymphoproliferative disorders that include primary cutaneous ALCL (C-ALCL) and lymphomatoid papulosis. The second group is systemic ALCL (S-ALCL), which is further divided into two subgroups: anaplastic lymphoma kinase positive (ALK+) and ALK-negative. Between 30% and 60% of S-ALCL express ALK, which is usually the result of a t(2;5) translocation that correlates with onset in the first three decades of life, male predominance, and good prognosis. Although morphologically similar, ALK- ALCL shows varied clinical behaviors and immunophenotypes; is commonly seen in older age groups, with a peak incidence in the sixth decade of life with no preference as to sex; and has an overall poorer prognosis. We present a case of CD30+, ALK- S-ALCL in a 7-year-old girl.
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PMID:Anaplastic large cell lymphoma: an unusual presentation in a 7-year-old girl. 2196 22

CD30-positive T-cell lymphoproliferative disorders are classified as cutaneous (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) or systemic. As extent of disease dictates prognosis and treatment, patients with skin involvement need clinical staging to determine whether systemic lymphoma also is present. Similar processes may involve mucosal sites of the head and neck, constituting a spectrum that includes both neoplasms and reactive conditions (eg, traumatic ulcerative granuloma with stromal eosinophilia). However, no standard classification exists for mucosal CD30-positive T-cell lymphoproliferations. To improve our understanding of these processes, we identified 15 such patients and examined clinical presentation, treatment and outcome, morphology, phenotype using immunohistochemistry, and genetics using gene rearrangement studies and fluorescence in situ hybridization. The 15 patients (11 M, 4 F; mean age, 57 years) had disease involving the oral cavity/lip/tongue (9), orbit/conjunctiva (3) or nasal cavity/sinuses (3). Of 14 patients with staging data, 7 had mucosal disease only; 2 had mucocutaneous disease; and 5 had systemic anaplastic large cell lymphoma. Patients with mucosal or mucocutaneous disease only had a favorable prognosis and none developed systemic spread (follow-up, 4-93 months). Three of five patients with systemic disease died of lymphoma after 1-48 months. Morphologic and phenotypic features were similar regardless of extent of disease. One anaplastic lymphoma kinase-positive case was associated with systemic disease. Two cases had rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3, seen most frequently in primary cutaneous anaplastic large cell lymphoma. Our findings suggest mucosal CD30-positive T-cell lymphoproliferations share features with cutaneous CD30-positive T-cell lymphoproliferative disorders, and require clinical staging for stratification into primary and secondary types. Primary cases have clinicopathologic features closer to primary cutaneous disease than to systemic anaplastic large cell lymphoma, including indolent clinical behavior. Understanding the spectrum of mucosal CD30-positive T-cell lymphoproliferations is important to avoid possible overtreatment resulting from a diagnosis of overt T-cell lymphoma.
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PMID:Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders. 2238 54

Anaplastic large cell cutaneous lymphomas are clinically and pathologically heterogeneous, CD30 + (Ki-1) lymphoproliferative disorders. The importance of anaplastic lymphoma kinase (ALK) positivity is well known in the prognosis of primary systemic anaplastic large cell cutaneous lymphomas; however, the same in primary cutaneous anaplastic large cell cutaneous lymphomas is not much clear. Herein we report a 65-year-old male with an 18-month history of minimally pruritic localized nodulo-plaque lesion over lower back. Histology revealed cutaneous large cell lymphoma and immunohistochemical staining showed positivity for CD30, CD3 and ALK. The role of ALK positivity in pcALCL is discussed in this article.
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PMID:Anaplastic lymphoma kinase-positive primary cutaneous anaplastic large cell lymphoma--is it a new variant? 2256 37

Anaplastic large cell lymphomas are peripheral T-cell lymphomas that are characterized by a proliferation of large anaplastic blasts expressing CD30. In children, systemic anaplastic large cell lymphomas often present at advanced clinical stage and harbor translocations involving the anaplastic lymphoma kinase (ALK) gene leading to the expression of chimeric anaplastic lymphoma kinase (ALK)-fusion proteins. Primary cutaneous anaplastic large cell lymphoma is regarded as an ALK-negative variant confined to the skin and is part of the spectrum of primary cutaneous CD30-positive T-cell lymphoproliferative disorders. Thirty-three of 487 pediatric patients registered within the Anaplastic Large Cell Lymphoma-99 trial (1999 to 2006) presented with a skin limited CD30-positive lympho-proliferative disorder. In 23 of the 33 patients, material for international histopathological review was available, and the cases were studied for histopathological, immunophenotypical and clinical features as well as for breaks within the ALK gene. Five of 23 cases and one additional case (identified after closure of the trial) expressed ALK-protein. Complete staging excluded any other organ involvement in all children. Expression of ALK proteins was demonstrated by immunohistochemistry in all cases and the presence of breaks of the ALK gene was genetically confirmed in 5 evaluable cases. The histopathological and clinical picture of these skin-restricted ALK-positive lymphomas was indistinguishable from that of cutaneous anaplastic large cell lymphoma. Five children presented with a single skin lesion that was completely resected in 4 and incompletely resected in one. Three of these patients received no further therapy, 2 additional local radiotherapy, and one chemotherapy. All children remain in complete remission with a median follow up of seven years (range 1-8 years). We present 6 pediatric cases of ALK-positive primary cutaneous anaplastic large cell lymphomas. After thorough exclusion of systemic involvement, therapy confined to local measures seems to be sufficient to induce cure.
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PMID:ALK-positive anaplastic large cell lymphoma limited to the skin: clinical, histopathological and molecular analysis of 6 pediatric cases. A report from the ALCL99 study. 2277 5

BRAF V600E mutations are present in virtually all cases of hairy cell leukemia (HCL). We hypothesized that detection of phospho-ERK (pERK) in tissue sections may be a useful marker for diagnosis of HCL. pERK/CD20 double immunostaining was performed on 90 formalin-fixed bone marrow trephine samples affected with small B-cell lymphoproliferative disorders, including 28 cases of HCL. pERK staining was observed in all 28 cases of HCL and in 1 of 62 cases of non-HCL B-cell lymphoproliferative disorders. By allele-specific polymerase chain reaction, all 11 cases of HCL with available DNA were positive for BRAF V600E, as was the 1 pERK non-HCL case. The remaining 31 non-HCL cases tested were negative for BRAF V600E. The sensitivity and specificity of pERK for diagnosis of HCL was 100% and 98%, respectively. We conclude that the presence of pERK as detected by immunohistochemical staining is a useful surrogate marker for BRAF V600E in the diagnosis of HCL.
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PMID:Phospho-ERK(THR202/Tyr214) is overexpressed in hairy cell leukemia and is a useful diagnostic marker in bone marrow trephine sections. 2321 Dec 89

Current laboratory technics, clinicopathologic findings cannot always reliably distinguish primary cutaneous CD30(+) lymphoproliferative disorders (LPD), such as lymphomatoid papulosis (LyP), primary cutaneous CD30(+) anaplastic large cell lymphoma (PCALCL), transformed mycosis fungoides (T-MF) and systemic ALK(-) anaplastic large cell lymphoma (ALCL) with skin involvement. We investigated the presence of IRF4 translocation with break apart DNA-FISH method of these entities according to the recent studies of Feldman et al. In our study group with 53 cases, the detection of IRF4 translocation had a specificity and positive predictive value for PCALCL of 100%. In contrast MUM1/IRF4 protein expression was distributed widely without any predictive value.
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PMID:The significance of MUM1/IRF4 protein expression and IRF4 translocation of CD30(+) cutaneous T-cell lymphoproliferative disorders: a study of 53 cases. 2333 72

CD30(+) lymphoproliferative disorders represent a spectrum of diseases with distinct clinical phenotypes ranging from reactive conditions to aggressive systemic anaplastic lymphoma kinase (ALK)(-) anaplastic large cell lymphoma (ALCL). In January 2011, the U.S. Food and Drug Administration (FDA) announced a possible association between breast implants and ALCL, which was likened to systemic ALCL and treated accordingly. We analyzed existing data to see if implant-associated ALCL (iALCL) may represent a distinct entity, different from aggressive ALCL. We conducted a systematic review of publications regarding ALCL and breast implantation for 1990-2012 and contacted corresponding authors to obtain long-term follow-up where available. We identified 44 unique cases of iALCL, the majority of which were associated with seroma, had an ALK(-) phenotype (97%), and had a good prognosis, different from the expected 40% 5-year survival rate of patients with ALK(-) nodal ALCL (one case remitted spontaneously following implant removal; only two deaths have been reported to the FDA or in the scientific literature since 1990). The majority of these patients received cyclophosphamide, doxorubicin, vincristine, and prednisolone with or without radiation, but radiation alone also resulted in complete clinical responses. It appears that iALCL demonstrates a strong association with breast implants, a waxing and waning course, and an overall good prognosis, with morphology, cytokine profile, and biological behavior similar to those of primary cutaneous ALCL. Taken together, these data are suggestive that iALCL may start as a reactive process with the potential to progress and acquire an aggressive phenotype typical of its systemic counterpart. A larger analysis and prospective evaluation and follow-up of iALCL patients are necessary to definitively resolve the issue of the natural course of the disease and best therapeutic approaches for these patients.
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PMID:Breast implant-associated ALCL: a unique entity in the spectrum of CD30+ lymphoproliferative disorders. 2342 41

Hairy cell leukemia (HCL) is an uncommon chronic leukemia of mature B cells. Leukemic B cells of HCL exhibit a characteristic morphology and immunophenotype and coexpress multiple clonally related immunoglobulin isotypes. Precise diagnosis and detailed workup is essential, because the clinical profile of HCL can closely mimic that of other chronic B-cell lymphoproliferative disorders that are treated differently. Variants of HCL, such as HCLv and VH4-34 molecular variant, vary in the immunophenotype and specific VH gene usage, and have been more resistant to available treatments. On the contrary, classic HCL is a highly curable disease. Most patients show an excellent long-term response to treatment with single-agent cladribine or pentostatin, with or without the addition of an anti-CD20 monoclonal antibody such as rituximab. However, approximately 30-40 % of patients with HCL relapse after therapy; this can be treated with the same purine analogue that was used for the initial treatment. Advanced molecular techniques have identified distinct molecular aberrations in the Raf/MEK-ERK pathway and BRAF (V600E) mutations that drive the proliferation and survival of HCL B cells. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. Ongoing and planned clinical trials are assessing various treatment strategies, such as the combination of purine analogues and various anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22 (e.g., moxetumomab pasudotox), BRAF inhibitors, such as vemurafenib, and B-cell receptor signaling inhibitors, such as ibrutinib, which is a Bruton's tyrosine kinase inhibitor. This article provides an update of our current understanding of the pathophysiology of HCL and the treatment options available for patients with classic HCL. Discussion of variant forms of HCL is beyond the scope of this manuscript.
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PMID:Update on the biology and treatment options for hairy cell leukemia. 2465 20

Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.
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PMID:Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders. 2480 54


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