Gene/Protein Disease Symptom Drug Enzyme Compound
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The clinicopathological and biological significance of Hodgkin's disease and non-Hodgkin's lymphoma, which are infrequently encountered in women of childbearing age, remains to be clarified. We recently reviewed 4 cases of non-Hodgkin's lymphoma of the T/natural killer (T/NK)-cell phenotype, all of which were associated with pregnancy and characterized by the expression of the cytotoxic granule-associated proteins T-cell intracellular antigen-1 and/or granzyme B. The 4 cases selected had presented between November 1993 and May 1999. The criteria for selection were that the onset of clinical manifestations occurred during pregnancy or within 6 months after delivery. The patients comprised 1 patient with p80/anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), 1 with p80/ALK-negative ALCL, and 2 with peripheral T/NK-cell lymphomas of unspecified type. The diseases followed aggressive clinical courses: 3 patients died within 6.5 months after diagnosis, and only 1 was still alive with the disease 17 months after diagnosis. The diseases appeared to progress rapidly after delivery. Maternal immunity and hormonal changes during pregnancy may be closely related to the biological behavior of these unusual tumors. This study is, to the best of our knowledge, the first to address pregnancy-associated cytotoxic lymphoma.
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PMID:Pregnancy-associated cytotoxic lymphoma: a report of 4 cases. 1159 20

Anaplastic large-cell lymphoma (ALCL) comprises a group of non-Hodgkin's lymphomas (NHLs) that were first described in 1985 by Stein and co-workers and are characterized by the expression of the CD30/Ki-1 antigen (Stein et al., 1985). Approximately half of these lymphomas are associated with a typical chromosomal translocation, t(2;5)(p23;q35). Much confusion about the exact classification and clinicopathological features of this subgroup of NHL was clarified with the identification of NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) as the oncogene created by the t(2;5) (Morris et al., 1994). With the discovery of NPM-ALK as the specific lymphoma gene mutation, this NHL subtype could be redefined on the molecular level. This achievement was enhanced by the availability of specific antibodies that recognize ALK fusion proteins in paraffin-embedded lymphoma tissues. Several excellent recent reviews have summarized the histopathological and molecular findings of ALCL and their use in the classification of this lymphoma entity (Anagnostopoulos and Stein, 2000; Benharroch et al., 1998; Drexler et al., 2000; Foss et al., 2000; Gogusev and Nezelof, 1998; Kadin and Morris, 1998; Ladanyi, 1997; Morris et al., 2001; Shiota and Mori, 1996; Skinnider et al., 1999; Stein et al., 2000). This review will focus on the molecular function and signal transduction pathways activated by ALK fusion oncogenes, with recent advances and possible clinical implications to be discussed.
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PMID:Translocations involving anaplastic lymphoma kinase (ALK). 1160 14

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R, TEL/TRKC(L), and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic leukemias and non-Hodgkin's lymphoma. FTK-transformed cells displayed drug resistance against the cytostatic drugs cisplatin and mitomycin C. These cells were not protected from drug-mediated DNA damage, implicating activation of the mechanisms preventing DNA damage-induced apoptosis. Various FTKs, except TEL/TRKC(L), can activate STAT5, which may be required to induce drug resistance. We show that STAT5 is essential for FTK-dependent upregulation of RAD51, which plays a central role in homology-dependent recombinational repair (HRR) of DNA double-strand breaks (DSBs). Elevated levels of Rad51 contributed to the induction of drug resistance and facilitation of the HRR in FTK-transformed cells. In addition, expression of antiapoptotic protein Bcl-xL was enhanced in cells transformed by the FTKs able to activate STAT5. Moreover, cells transformed by all examined FTKs displayed G(2)/M delay upon drug treatment. Individually, elevated levels of Rad51, Bcl-xL, or G(2)/M delay were responsible for induction of a modest drug resistance. Interestingly, combination of these three factors in nontransformed cells induced drug resistance of a magnitude similar to that observed in cells expressing FTKs activating STAT5. Thus, we postulate that RAD51-dependent facilitation of DSB repair, antiapoptotic activity of Bcl-xL, and delay in progression through the G(2)/M phase work in concert to induce drug resistance in FTK-positive leukemias and lymphomas.
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PMID:Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. 1202 32

Phenotypic and genotypic analyses of cells are increasingly essential for understanding pathogenetic mechanisms as well as for diagnosing and classifying malignancies and other diseases. We report a novel multicolor approach based on the FICTION (fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms) technique, which enables the simultaneous detection of morphological, immunophenotypic, and genetic characteristics of single cells. As prerequisite, multicolor interphase fluorescence in situ hybridization assays for B-cell non-Hodgkin's lymphoma and anaplastic large-cell lymphoma have been developed. These assays allow the simultaneous detection of the most frequent primary chromosomal aberrations in these neoplasms, such as t(8;14), t(11;14), t(14;18), and t(3;14), and the various rearrangements of the ALK gene, respectively. To establish the multicolor FICTION technique, these assays were combined with the immunophenotypic detection of lineage- or tumor-specific antigens, namely CD20 and ALK, respectively. For evaluation of multicolor FICTION experiments, image acquisition was performed by automatic sequential capturing of multiple focal planes. Thus, three-dimensional information was obtained. The multicolor FICTION assays were applied to well-characterized lymphoma samples, proving the performance, validity, and diagnostic power of the technique. Future multicolor FICTION applications include the detection of preneoplastic lesions, early stage and minimal residual diseases, or micrometastases.
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PMID:Multicolor-FICTION: expanding the possibilities of combined morphologic, immunophenotypic, and genetic single cell analyses. 1216 66

Patients with relapsed aggressive lymphoma after high dose chemotherapy have a very poor prognosis and long-term survival is rare. Most patients are not eligible for allogeneic stem cell transplantation in this setting and treatment, therefore, becomes palliative. A few studies have shown that trofosfamide, an oral alkylating agent, may be effective as palliative treatment in non-Hodgkin's lymphoma. Trofosfamide therapy is considered rather non-toxic with an overall response rate from 50 to 80%. Most responses are, however, partial and their duration is short. We report a patient with a very aggressive ALK + anaplastic large cell lymphoma (ALCL), relapsing shortly after high dose chemotherapy. Unrelated allogeneic transplantation was hot possible. After several radio/chemotherapy regimens trofosfamide was started as palliative treatment. This therapy resulted in a complete remission, still ongoing, 27 months after termination of intravenous cytotoxic therapy and 16 months after withdrawal of trofosfamide. Thus, in this particular case, trofosfamide turned out to be an unexpectedly effective salvage therapy for an otherwise very aggressive relapsing ALCL.
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PMID:Trofosfamide as salvage therapy for anaplastic large cell lymphoma relapsing after high-dose chemotherapy. 1261 23

Nuclear factor kappaB-inducing kinase (NIK) is a member of the MAP kinase kinase kinase family that was first identified as a component of the TNF-R1-induced NF-kappaB activation pathway (TNF, tumor necrosis factor; nuclear factor kappaB, NF-kappaB). Gene knockout study, however, suggests that NIK is dispensable for TNF-R1- but required for lymphotoxin-beta receptor-induced NF-kappaB activation. A NIK kinase inactive mutant is a potent inhibitor of NF-kappaB activation triggered by various stimuli, suggesting that NIK is involved in a broad range of NF-kappaB activation pathways. To unambiguously identify signaling pathways that NIK participates in, we screened antibody arrays for proteins that are associated with NIK. This effort identified ErbB4, one of the EGF/heregulin receptors, and Grb7, an adapter protein associated with ErbB4 (ErbB, epidermal growth factor receptor family protein; EGF, epidermal growth factor; Grb, growth factor receptor bound). Coimmunoprecipitation experiments demonstrated that NIK interacted with Grb7, as well as Grb10 and Grb14, but not Grb2. Domain mapping experiments indicated that the central GM domain of Grb7 was sufficient for its interaction with NIK. Coimmunoprecipitation experiments also indicated that Grb7 and NIK could be simultaneously recruited into signaling complexes of all known EGF/heregulin receptors, including EGFR, ErbB2, ErbB3, and ErbB4. In reporter gene assays, NIK could potentiate Grb7, ErbB2/ErbB4, and EGF-induced NF-kappaB activation. A NIK kinase inactive mutant could block ErbB2/ErbB4 and EGF-induced NF-kappaB activation. Moreover, EGF/heregulin receptors activated NF-kappaB in wild-type, but not NIK-/- embryonic fibroblasts. Our findings suggest that NIK is a component of the EGF/heregulin receptor signaling complexes and involved in NF-kappaB activation triggered by these receptors.
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PMID:NIK is a component of the EGF/heregulin receptor signaling complexes. 1285 71

The Drosophila melanogaster gene Anaplastic lymphoma kinase (Alk) is homologous to mammalian Alk, which encodes a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs). In humans, the t(2;5) translocation, which involves the ALK locus, produces an active form of ALK, which is the causative agent in non-Hodgkin's lymphoma. The physiological function of the Alk RTK, however, is unknown. In this paper, we describe loss-of-function mutants in the Drosophila Alk gene that cause a complete failure of the development of the gut. We propose that the main function of Drosophila Alk during early embryogenesis is in visceral mesoderm development.
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PMID:A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster. 1285 99

Anaplastic large cell lymphoma (ALCL) is a neoplasm of activated lymphocytes, commonly expressing T-cell antigens and cytotoxic proteins. Histopathology reveals distinctive infiltration of sinuses and paracortical T-cell-rich regions of lymph nodes by tumor cells which have abundant cytoplasm and large irregular/convoluted nuclei, and which are frequently multinucleated with prominent nucleoli. ALCL often presents in advanced clinical stages with B symptoms; extranodal disease occurs in 40% of patients. The pathogenesis of systemic ALCL is linked to phosphorylation of a tyrosine kinase (ALK) resulting in unregulated growth of affected lymphoid cells. ALK is activated through chromosomal translocations/inversions with any of several partner genes, most commonly nucleophosmin (NPM). Downstream signal transduction pathway(s) are not fully defined but appear to involve phospholipase Cgamma, phosphatidylinositol (PI)3K/Akt, and STAT-3 and STAT-5 proteins. Primary cutaneous ALCL appears to have a different pathogenesis and better prognosis than does systemic ALCL, presenting as one or more skin tumors, usually localized. Excision or local irradiation is usually effective treatment. A clinically benign variant of primary cutaneous ALCL is lymphomatoid papulosis (LyP), characterized by recurrent crops of papules/nodules up to 2 cm in diameter which undergo spontaneous regression. LyP is managed by observation, ultraviolet light therapy, or low-dose methotrexate. LyP patients have a predisposition to develop malignant lymphomas, including Hodgkin's lymphoma, mycosis fungoides, and non-Hodgkin's lymphoma, by as yet unknown mechanisms. The prognosis for patients with LyP is otherwise excellent.
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PMID:Systemic and primary cutaneous anaplastic large cell lymphomas. 1287 73

T/null-cell anaplastic large cell lymphoma (ALCL) is a morphologically and clinically heterogeneous group of non-Hodgkin's lymphoma; to date several morphologic variants have been described on histologic specimens. However, the cytologic features of these variants in the fine-needle aspiration (FNA) specimens have not been well evaluated. The t(2;5)(p23;q35) has been identified in a subset of T/null-ALCL and is known to be associated with a favorable prognosis. We reviewed the cytomorphologic characteristics in 24 FNA specimens of ALCL. In all cases, the diagnosis was confirmed on histologic specimens, and immunohistochemical studies for anaplastic lymphoma kinase (ALK) protein expression were performed on the aspirates. The presence of ALK breakpoints were evaluated in nine cases, using a DNA break-apart probe on chromosome 2 covering the ALK gene by fluorescence in situ hybridization (FISH) techniques. Two hundred cells per case were examined. The results were expressed as the percentage of cells containing more than two signals of chromosome 2 to the total number of cells counted. FNA sites included lymph nodes (20), lung (2), breast (1), and soft tissue (1). The median age of the patients was 56 yr (range, 17-75 yr). Twenty cases had systemic involvement; in four cases, skin was the primary site with secondary involvement of the lymph nodes. All cases were CD30(+) by immunohistochemistry; 20 were of T-cell phenotype and 4 were null cell type. The cytologic evaluation revealed typical anaplastic morphology (common type) with many "hallmark cells" in 16 (67%) cases. Other morphologic variants identified were small cell pattern in five cases, monomorphic pattern in two cases, and lymphohistiocytic pattern in one case. FISH studies showed that six (66.7%) of nine cases had at least two signals of chromosome 2, consistent with ALK breakpoints. With careful cytomorphologic evaluation in conjunction with appropriate immunohistochemical studies, a diagnosis of ALCL can be confidently made in the FNA specimens in the cellular aspirates and its morphologic variants also can be recognized. Furthermore, the FNA specimen is suitable in detecting ALK breakpoints by FISH study, permitting rapid identification of a subset of patients with ALCL, who may have a favorable prognosis. Using a commercially available probe, detection of ALK breakpoints in the FNA specimens is simple and can be a useful diagnostic adjunct in cases where distinction from other lymphomas or lymphoid lesions is morphologically difficult.
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PMID:Detection of a subset of CD30+ anaplastic large cell lymphoma by interphase fluorescence in situ hybridization. 1288 41

Natural killer and natural killer-like T cell lymphomas represent a rare type of non-Hodgkin's lymphoma originally described to involve the upper aerodigestive tract. This malignancy has been increasingly observed in other extranodal sites, particularly in the skin. Patients with cutaneous natural killer cell lymphoma generally have a poor prognosis; however, the etiology and the underlying molecular pathogenesis remain unclear. This study aimed to investigate comprehensively genomic changes in blastic natural killer and extranodal natural killer-like T cell lymphoma with cutaneous involvement. Comparative genomic hybridization showed chromosome imbalances in six of eight cases studied (75%). The mean number of chromosome imbalances per sample was 2.18+/-1.63 with similar number of gains (1.18+/-1.17) and losses (1.00+/-1.34). The most frequent DNA copy number changes observed were losses of 9/9p (83%), followed by loss of 13q and gain of 7 (67%). Similar patterns of chromosome imbalances were observed in both blastic natural killer and cutaneous natural killer-like T cell lymphomas. Loss of the RB1 gene at 13q14.2 was detected in one blastic natural killer cell lymphoma with 13q loss using a gene dosage assay, and in one cutaneous natural killer-like T cell lymphoma without 13q loss using fluorescent in situ hybridization. Genomic microarray analysis identified oncogene copy number gains of PAK1 and JUNB in three of four cases studied, and gains of RAF1, CTSB, FGFR1, and BCR in two cases. Real-time polymerase chain reaction detected amplification of CTSB and RAF1 in four of five cases analyzed, JUNB and MYCN in three cases, and REL and YES1 in two cases, respectively. In conjunction with this study, an extensive literature search for the published G-banded karyotypes of four subsets of natural killer cell lymphomas was conducted, which showed a nonrandom pattern of multiple chromosome aberrations. These results reveal consistent genetic alterations in cutaneous natural killer cell lymphomas, and provide a basis for further investigation of molecular pathogenesis in this malignancy.
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PMID:Genomic alterations in blastic natural killer/extranodal natural killer-like T cell lymphoma with cutaneous involvement. 1292 24


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