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PubMed2006

In vivo T-cell immune response against anaplastic lymphoma kinase in patients with anaplastic large cell lymphomas.

BACKGROUND AND OBJECTIVES: Anaplastic lymphoma kinase (ALK) oncogenic fusion proteins, expressed in about 60% of anaplastic large cell lymphomas (ALCL), are tumor-specific molecular targets for such a malignancy. One of the promising ALK-targeted therapeutic options is cancer vaccination. In this study, we investigate whether ALK is a tumor-associated antigen suitable for immune interventions. DESIGN AND METHODS: The frequency and the functional phenotype of the anti-ALK CD8 precursor repertoire in freshly isolated peripheral blood mononuclear cells (PBMC) from healthy donors and ALK-positive patients were determined by major histocompatibility complex (MHC)/tetrameric analyses. The anti-ALK secondary immune responses were evaluated as PBMC-specific interferon (INF-gamma) release by ELISPOT. In addition, the ability of the anti-ALK immune response to specifically lyse ALK-positive lymphoma cells was investigated by in vitro stimulation with ALK-derived peptide p280-89. RESULTS: Tetrameric MHC/peptide complexes revealed high frequencies of CD8/ALK-tetramer-positive cells both in patients and in healthy individuals. However, the functional phenotype of the CD8/ALK-tetramer-positive lymphocytes showed the presence of effector and memory T lymphocytes only in patients. The anti-ALK cytotoxic T lymphocytes (CTL) of patients, but not healthy donors, displayed thresholds of activation comparable to those of CTL precursors of a recall antigen (influenza virus). A polyclonal ALK-specific tumor-reactive T-cell line was isolated from patients' peripheral blood lymphocytes. INTERPRETATION AND CONCLUSIONS: The presence of an anti-ALK effector/memory lymphocyte population in the peripheral blood of ALK-positive patients indicates an in vivo antigenic challenge. Thus, ALK is a lymphoma-associated antigen suitable for immune interventions. The high number of anti-ALK memory CD8 T cells present in patients' PBMC may represent a valid source of activated CTL suitable for cancer cell lysis.

Anaplastic Lymphoma Kinase↗
PubMed2004

Expression of anaplastic lymphoma kinase in soft tissue tumors: an immunohistochemical and molecular study of 249 cases.

Although anaplastic lymphoma kinase (ALK) has been considered a diagnostic marker specifying a subset of anaplastic large cell lymphomas and inflammatory myofibroblastic tumors (IMTs), the existence of this receptor in some other mesenchymal malignancies has been recently reported. We examined a wider variety of soft tissue tumors to further advance the survey of ALK status in mesenchymal lesions. ALK protein expression was evaluated immunohistochemically with 2 specific antibodies (ALK1 and 5A4) in 249 benign and malignant soft tissue tumors, and the expression of ALK transcripts and 8 types of ALK fusion transcripts was assessed using reverse transcription-polymerase chain reaction (RT-PCR) in 165 and 100 tumors, respectively. Moreover, ALK gene status was analyzed by interphase fluorescence in situ hybridization (FISH) in 17 tumors with ALK expression. Immunohistochemically, ALK protein was detected in 69 cases (28%), including IMTs (4 of 4), rhabdomyosarcomas (4 of 7), various lipogenic tumors (35 of 65), Ewing's sarcoma/peripheral primitive neuroectodermal tumors (6 of 10), malignant fibrous histiocytomas (8 of 37), leiomyosarcomas (3 of 18), and other non-IMT tumors (9 of 108); however, most of these, except the IMTs, displayed merely low-level expression. Although ALK transcripts were identified in 85 (52%) of the 165 cases examined by RT-PCR, the full-length (wild-type) ALK, rather than the truncated or chimeric forms detected in IMTs, predominated in most non-IMT tumors. Except for 2 IMTs, all cases with the expression of ALK messages displayed no detectable ALK fusion transcripts. More than 67% of the cases analyzed by both RT-PCR and immunohistochemical assays demonstrated concordant results. ALK gene amplification was found in 4 non-IMT tumors (2 leiomyosarcomas and 1 case each of rhadomyosarcoma and malignant fibrous histiocytoma) analyzed by FISH, and the rearrangement of this gene was identified in 2 IMTs. The current data expands the variety of non-IMT soft tissue tumors with ALK expression, and warrants further investigation of its underlying molecular mechanisms.

Anaplastic Lymphoma Kinase↗
PubMed1997

Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.

The NPM-ALK fusion gene, formed by the t(2;5)(p23;q35) translocation in non-Hodgkin's lymphoma, encodes a 75-kDa hybrid protein that contains the amino-terminal 117 amino acid residues of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase). Here, we demonstrate the transforming ability of NPM-ALK and show that oncogenesis by the chimeric protein requires the activation of its kinase function as a result of oligomerization mediated by the NPM segment. Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM. Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments. Immunostaining performed with both polyclonal and monoclonal anti-ALK antibodies confirmed the dual location of the oncoprotein and also indicated that NPM-ALK is abundant within both the nucleoplasm and the nucleolus. An intact NPM segment is absolutely required for NPM-ALK-mediated oncogenesis, as indicated by our observation that three different NPM-ALK mutant proteins lacking nonoverlapping portions of the NPM segment were each unable to form complexes, lacked kinase activity in vivo, and failed to transform cells. However, NPM could be functionally replaced in the fusion protein with the portion of the unrelated translocated promoter region (TPR) protein that activates the TPR-MET fusion kinase by mediating dimerization through its leucine zipper motif. This engineered TPR-ALK hybrid protein, which transformed cells almost as efficiently as NPM-ALK, was localized solely within the cytoplasm of cells. These data indicate that the nuclear and nucleolar localization of NPM-ALK, which probably occur because of transport via the shuttling activity of NPM, is not required for oncogenesis. Further, the activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.

Anaplastic Lymphoma Kinase↗
PubMed1993

Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity.

Human cDNA clones encoding four novel putative transmembrane protein serine/threonine kinases, denoted activin receptor-like kinase (ALK) -1, -2, -3 and -4, were obtained using a polymerase chain reaction (PCR)-based strategy. The PCR primers were designed based upon the sequence similarity between the activin receptor type II and Daf-1. The cDNA clones for ALK-1, -2 and -3 encode complete proteins of 503, 509 and 532 amino acids respectively. The ALK-4 cDNA is incomplete and the predicted protein of 383 amino acids has a truncated extracellular domain. The ALKs share similar domain structures, comprising predicted signal sequences at the N-terminals, followed by hydrophilic cysteine-rich ligand-binding domains, single hydrophobic transmembrane regions and C-terminal intracellular portions that consist almost entirely of putative serine/threonine kinase domains. The ALKs have approximately 40% sequence identity to activin receptors type II and IIB, transforming growth factor-beta (TGF-beta) type II receptor and Daf-1 in the kinase domains. However, the sequence identities are higher (60-79%) between ALK-1, -2, -3 and -4, suggesting that they form a subfamily among the putative receptor serine/threonine kinases. The extracellular domains of ALKs show only little sequence identity to other putative receptor serine/threonine kinases, but the cysteine residues are conserved. Their structural properties suggest that ALK-1 to -4 are receptors that may bind ligands that are members of the TGF-beta superfamily. The expression of mRNA in human tissues varied for the different ALKs; ALK-2 and ALK-4 showed ubiquitous tissue expression patterns, whereas the distribution of ALK-1 and ALK-3 varied strongly between different tissues with more restricted expression patterns. These results suggest that each ALK may have different in vivo functions.

Activin Receptors↗
PubMed2003

Inflammatory myofibroblastic tumor with predominant anaplastic lymphoma kinase-positive cells lacking a myofibroblastic phenotype.

Inflammatory myofibroblastic tumor (IMT), synonymously referred to as inflammatory pseudotumor, is a distinctive mesenchymal lesion composed of spindle cells displaying morphological features of myofibroblasts admixed with considerable numbers of inflammatory cells. Recent genetic and molecular studies have shown that a subset of IMT is characterized by the expression of altered anaplastic lymphoma kinase (ALK) protein mostly resulting from rearrangements of the ALK gene such as TPM3-ALK, TPM4-ALK and CLTC-ALK fusion genes. We analyzed the ALK status in nine cases of IMT arising in various anatomical locations. Six cases showed immunohistochemical expression of the ALK protein, and two ALK-positive lesions examined by reverse transcription-polymerase chain reaction and a subsequent sequencing analysis harbored the TPM4-ALK fusion gene. Of note, the majority of ALK-positive tumor cells in four of the six lesions lacked the coexpression of myogenic markers including alpha-smooth muscle actin, a cytoskeletal protein indicating myofibroblastic differentiation, whereas a substantial number of tumor cells in the remaining two cases coexpressed ALK and alpha-smooth muscle actin and/or desmin. In an ultrastructural study of the lesion with predominant ALK-positive/actin-negative cells, spindle cells failed to demonstrate features of myofibroblasts such as intracytoplasmic bundles of thin filaments and dense bodies. The current findings suggest that ALK-positive cells in IMT are not always myofibroblastic but might be immature primitive mesenchymal cells.

Adult↗
PubMed2026

Anaplastic lymphoma kinase immunohistochemical positivity in high-grade pulmonary neuroendocrine carcinoma: an actionable signal or merely a shadow?

AIMS: Anaplastic lymphoma kinase (ALK) rearrangements are actionable drivers in non-small cell lung carcinoma (NSCLC), but the biological significance of ALK-immunohistochemistry (IHC) positivity in high-grade pulmonary neuroendocrine carcinoma (NEC) remains unclear. This study evaluated the diagnostic and therapeutic implications of discordant ALK IHC and genomic findings and the role of multimodal molecular testing in resolving them. METHODS: We retrospectively analysed eight South Asian patients (Indian and Nepali) with de novo high-grade pulmonary NEC and diffuse ALK immunoreactivity treated at a tertiary cancer centre in India. Comprehensive molecular profiling using DNA- and RNA-based next-generation sequencing (NGS) and ALK fluorescence in situ hybridisation (where tissue was adequate) was performed. Clinical outcomes and responses to ALK-targeted tyrosine kinase inhibitors (TKIs) were assessed. RESULTS: ALK IHC positivity was observed in 8 of 100 selectively tested cases among 319 high-grade pulmonary NECs diagnosed between 2019 and 2025. The cohort included seven SCLCs (one combined adenocarcinoma-SCLC) and one large-cell neuroendocrine carcinoma (LCNEC). Median age was 51 years; 75% were female and 87.5% never-smokers. Among five comprehensively profiled cases, true ALK rearrangements were confirmed in two (one LCNEC and one SCLC), both detectable only by RNA sequencing. Durable benefit from ALK-TKI therapy was seen only in the molecularly confirmed LCNEC case (>16 months), whereas ALK IHC-positive but NGS-negative cases progressed rapidly. CONCLUSIONS: True ALK rearrangements in high-grade pulmonary NEC are rare but highly actionable. ALK IHC alone is an unreliable predictor of therapeutic benefit. RNA-based sequencing is essential for fusion detection. Comprehensive molecular confirmation, with RNA sequencing as the preferred modality, should precede any initiation of ALK-targeted therapy in high-grade pulmonary NEC.

IMMUNOHISTOCHEMISTRY↗
PubMed2004

Multi-lineage interrogation of the performance characteristics of a split-signal fluorescence in situ hybridization probe for anaplastic lymphoma kinase gene rearrangements: a study of 101 cases characterized by immunohistomorphology on fixed archival tissue.

BACKGROUND: Fluorescence in situ hybridization (FISH) can identify chromosomal translocations on fixed archival tissue, but studies cross-validating the utility of FISH on lesions of different cell lineages that harbor similar translocations (e.g. those involving anaplastic lymphoma kinase [ALK]) have not been published. AIM: Our objective was to define the diagnostic utility, performance characteristics, and limitations of a commercially available, split-signal, FISH probe for ALK gene rearrangements on fixed, archived tissue from lesions of diverse cell lineage. STUDY DESIGN: The sensitivity, specificity, and positive and negative predictive values of the Vysis ALK FISH probe were compared with those of the ALK-1 antibody (Dako) in a series of 101 cases, comprising 43 hematolymphoid neoplasms, 4 reactive lymphoid controls, 50 non-hematolymphoid (including neuroectodermal, epithelial, myofibroblastic, and germ cell) lesions, and 4 early-trimester aborted fetuses that served as neuroblastic controls. METHODS: The study involved a predominantly (72%) Singaporean Chinese population aged between 9 months and 88 years (excluding the aborted fetal controls). All cases were reviewed both histologically and immunohistochemically with a wide panel of antibodies using the standard protocols in order to diagnose them according to the latest WHO classification systems. A positive cut-off value was determined, both by comparison with diagnostic categories with and without ALK translocations, as well as with negative controls. RESULTS: The ALK FISH probe suffered a 33% non-informative rate, but in informative cases it showed 94% concordance with the ALK-1 immunostain. A minimum cut-off value of 5 in 200 informative cells was adopted to make a positive call in each case. Of the ALK-1 immunoreactive lesions, nine lymphomas were concordantly ALK translocation-positive but one vesical inflammatory myofibroblastic tumor was discordantly FISH-negative. Among the ALK-1-immunonegative lesions, one case each of anaplastic lymphoma and pulmonary mycobacterial spindle cell pseudotumor were discordantly ALK FISH-positive, while a case each of intestinal myeloblastic tumor and ganglioglioma showed initial--but not reproducible--positive FISH readings. The remaining cases were concordantly negative. DISCUSSION: The discrepancies between ALK FISH results and well-established immunomorphological parameters indicate that interpretation is not always straightforward. Notably, the derivation of threshold cut-off values for positive calls on FISH assays has seldom been addressed in the literature, and has raised issues in interpreting cases with borderline positivity in this study. The factors that may influence such cut-off values are extensively reviewed. CONCLUSIONS: We propose the term 'conditional threshold positivity' to encourage the adoption of different cut-off values for making positive calls in lesions of different origin.

Adolescent↗
PubMed2003

ACE inhibition modulates transforming growth factor-beta receptors in the young rat.

The renin-angiotensin system plays an important role in renal growth and development. Exposure of the neonate to angiotensin converting enzyme (ACE) inhibitors increases mortality and results in growth retardation and abnormal renal development. It has been demonstrated that ACE inhibition in the developing kidney reduces the renal expression of growth factors, which may account for renal growth impairment. This study was designed to investigate the relationship between renal growth impairment and the expression of transforming growth factor-beta1 (TGF-beta1), TGF-beta receptor I [TbetaRI, activin-like kinase (ALK)-1 and ALK-5], and TGF-beta receptor II (TbetaRII). Newborn rat pups were treated with enalapril (30 mg/kg per day) or vehicle for 7 days, and kidneys were removed for Western blotting of TGF-beta1, ALK-1, ALK-5, and TbetaRII, and for RT-PCR of ALK-5 and TbetaRII. TGF-beta1, ALK-1, ALK-5, and TbetaRII were also detected by immunohistochemistry. Enalapril treatment resulted in an increased mortality (30.4%) by day 7, and reduced body weight and kidney weight ( P<0.05 versus vehicle). Enalapril decreased renal TGF-beta1, ALK-1, and ALK-5 protein expression ( P<0.05). Also, enalapril decreased ALK-5 mRNA expression ( P<0.05). TbetaRII expression was not changed by enalapril treatment. These results indicate that ACE inhibition in the developing kidney decreases TGF-beta1, ALK-1, and ALK-5 expression, which may account for renal growth impairment. TbetaRII may not be modulated by ACE inhibition in the developing kidney.

Activin Receptors, Type I↗
PubMed2002

The nucleophosmin-anaplastic lymphoma kinase fusion protein induces c-Myc expression in pediatric anaplastic large cell lymphomas.

The majority of pediatric anaplastic large cell lymphomas (ALCLs) carry the t(2;5)(p23;q35) chromosomal translocation that juxtaposes the dimerization domain of nucleophosmin with anaplastic lymphoma kinase (ALK). The nucleophosmin-ALK fusion induces constitutive, ligand-independent activation of the ALK tyrosine kinase leading to aberrant activation of cellular signaling pathways. To study the early consequences of ectopic ALK activation, a GyrB-ALK fusion was constructed that allowed regulated dimerization with the addition of coumermycin. Expression of the fusion protein caused a coumermycin-dependent increase in cellular tyrosine phosphorylation and c-Myc immunoreactivity, which was paralleled by a rise in c-myc RNA. To assess the clinical relevance of this observation, c-Myc expression was determined in pediatric ALK-positive and -negative lymphomas. Co-expression of c-Myc and ALK was seen in tumor cells in 15 of 15 (100%) ALK-positive ALCL samples, whereas no expression of either ALK or c-Myc was seen in six of six cases of ALK-negative T-cell lymphoma. C-Myc may be a downstream target of ALK signaling and its expression a defining characteristic of ALK-positive ALCLs.

Child↗
PubMed1998

Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity.

Large-cell anaplastic lymphoma is a subtype of non-Hodgkin's lymphoma characterized by the expression of CD30. More than half of these lymphomas have a chromosomal translocation, t(2;5), that leads to the expression of a hybrid protein comprised of the nucleolar phosphoprotein nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK). Here we show that transfection of the constitutively active tyrosine kinase NPM-ALK into Ba/F3 and Rat-1 cells leads to a transformed phenotype. Oncogenic tyrosine kinases transform cells by activating the mitogenic signal transduction pathways, e.g., by binding and activating SH2-containing signaling molecules. We found that NPM-ALK binds most specifically to the SH2 domains of phospholipase C-gamma (PLC-gamma) in vitro. Furthermore, we showed complex formation of NPM-ALK and PLC-gamma in vivo by coimmunoprecipitation experiments in large-cell anaplastic lymphoma cells. This complex formation leads to the tyrosine phosphorylation and activation of PLC-gamma, which can be corroborated by enhanced production of inositol phosphates (IPs) in NPM-ALK-expressing cells. By phosphopeptide competition experiments, we were able to identify the tyrosine residue on NPM-ALK responsible for interaction with PLC-gamma as Y664. Using site-directed mutagenesis, we constructed a comprehensive panel of tyrosine-to-phenylalanine NPM-ALK mutants, including NPM-ALK(Y664F). NPM-ALK(Y664F), when transfected into Ba/F3 cells, no longer forms complexes with PLC-gamma or leads to PLC-gamma phosphorylation and activation, as confirmed by low IP levels in these cells. Most interestingly, Ba/F3 and Rat-1 cells expressing NPM-ALK(Y664F) also show a biological phenotype in that they are not stably transformed. Overexpression of PLC-gamma can partially rescue the proliferative response of Ba/F3 cells to the NPM-ALK(Y664F) mutant. Thus, PLC-gamma is an important downstream target of NPM-ALK that contributes to its mitogenic activity and is likely to be important in the molecular pathogenesis of large-cell anaplastic lymphomas.

Animals↗
PubMed2006

Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes.

Anaplastic large cell lymphomas (ALCLs) represent a subset of lymphomas in which the anaplastic lymphoma kinase (ALK) gene is frequently fused to the nucleophosmin (NPM) gene. We previously demonstrated that the constitutive phosphorylation of ALK chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo and that ALK activity is strictly required for the survival of ALK-positive ALCL cells. To elucidate the signaling pathways required for ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of multiple ALK-positive ALCL cell lines, abrogating their ALK-mediated signaling by inducible ALK RNA interference (RNAi) or with potent and cell-permeable ALK inhibitors. Transcripts derived from the gene expression profiling (GEP) analysis uncovered a reproducible signature, which included a novel group of ALK-regulated genes. Functional RNAi screening on a set of these ALK transcriptional targets revealed that the transcription factor C/EBPbeta and the antiapoptotic protein BCL2A1 are absolutely necessary to induce cell transformation and/or to sustain the growth and survival of ALK-positive ALCL cells. Thus, we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions.

Anaplastic Lymphoma Kinase↗
PubMed2005

p130Cas mediates the transforming properties of the anaplastic lymphoma kinase.

Translocations of the anaplastic lymphoma kinase (ALK) gene have been described in anaplastic large-cell lymphomas (ALCLs) and in stromal tumors. The most frequent translocation, t(2;5), generates the fusion protein nucleophosmin (NPM)-ALK with intrinsic tyrosine kinase activity. Along with transformation, NPM-ALK induces morphologic changes in fibroblasts and lymphoid cells, suggesting a direct role of ALK in cell shaping. In this study, we used a mass-spectrometry-based proteomic approach to search for proteins involved in cytoskeleton remodeling and identified p130Cas (p130 Crk-associated substrate) as a novel interactor of NPM-ALK. In 293 cells and in fibroblasts as well as in human ALK-positive lymphoma cell lines, NPM-ALK was able to bind p130Cas and to induce its phosphorylation. Both of the effects were dependent on ALK kinase activity and on the adaptor protein growth factor receptor-bound protein 2 (Grb2), since no binding or phosphorylation was found with the kinase-dead mutant NPM-ALK(K210R) or in the presence of a Grb2 dominant-negative protein. Phosphorylation of p130Cas by NPM-ALK was partially independent from Src (tyrosine kinase pp60c-src) kinase activity, as it was still detectable in Syf-/- cells. Finally, p130Cas-/- (also known as Bcar1-/-) fibroblasts expressing NPM-ALK showed impaired actin filament depolymerization and were no longer transformed compared with wild-type cells, indicating an essential role of p130Cas activation in ALK-mediated transformation.

Anaplastic Lymphoma Kinase↗
PubMedDate not supplied

Comparison of laser in situ keratomileusis and automated lamellar keratoplasty for the treatment of myopia.

BACKGROUND: Automated lamellar keratoplasty (ALK) and laser in situ keratomileusis (LASIK) are surgical procedures used to correct high myopia, although their differences in effectiveness and long-term stability have not been sufficiently documented. Little information exists about the results of the two procedures in the hands of the same surgeon. METHODS: To assess long-term stability of refractive results of ALK and LASIK, a retrospective study of 260 eyes that received ALK and 308 eyes that received LASIK was undertaken. The mean follow-up was 1.8 years for ALK and 1.4 years for LASIK. RESULTS: The mean baseline spherical equivalent refraction in ALK eyes was -14.30 +/- 2.05 D (range -5 to -25 D) and in LASIK eyes was -8.50 +/- 1.75 D (range -3 to -26 D). At 3 months after surgery, 65 ALK eyes (25%) were within +/- 1.00 D of intended correction compared with 269 LASIK eyes (87.5%). At 1 year, only 31 ALK eyes (16%) were within +/- 1.00 D of intended correction, compared with 224 eyes (82%) in the LASIK group. At 3 months after surgery, the mean spherical equivalent refraction was -2.64 D in ALK eyes; at 1 year it was -4.60 D, and at 2 years it increased to -5.50 D. In contrast, the mean spherical equivalent refraction in the LASIK eyes at 3 months after surgery was -0.22 D and remained nearly stable until 1.5 years after surgery, when it was -0.50 D. More regression occurred when a large amount of corneal stromal tissue was removed. One out of four eyes that had more than 25% of its corneal tissue removed lost correction after 6 months for both ALK and LASIK. No ALK or LASIK eyes with a remaining corneal thickness of 310 microns or more had regression of the refractive result after 6 months. CONCLUSIONS: Both ALK and LASIK can reduce moderate and high myopia. The safety and long-term stability of LASIK is better than that for ALK. Although both procedures take advantage of lamellar keratoplasty techniques, the LASIK technique minimizes the depth of ablation while maximizing optical zone size which results in more accurate correction and better long-term stability, the latter depending primarily on the amount of corneal stromal tissue removed.

Adolescent↗
PubMed2003

[Anaplastic large-cell lymphoma: review].

Anaplastic large cell lymphomas (ALCLs) represent a heterogeneous group of malignant lymphoproliferative diseases. Most of the cases are of T-cell line with a loss of cell surface receptors but with a production of cytotoxic cytoplasmatic granules--immunohistochemically (IHC) positive perforin, granzyme B, and TIA-1. The diagnostics of ALCL is based on morphological findings and results of IHC, which further stratify ALCLs to basic immunophenotypes according to ALK (anaplastic lymphoma kinase) protein expression--ALCL CD30+ ALK+ and ALCL CD30+ ALK+. The morphological investigations are supplemented by karyotyping and/or by a demonstration of breakpoint at 2p23 harboring ALK gene (FISH), and by molecular detection of chimeric genes characteristic of ALK+ lymphomas (NPM-ALK, ATIC-ALK, TPM3-ALK, TFG-ALK, and some even rarer rearrangements). Molecular diagnostics is important in monitoring minimal residual disease. As some of the characteristic molecular changes were demonstrated in healthy individuals and in Hodgkin's disease by quantitative PCR, the validation of these findings demands further studies. ALK protein positive ALCLs affect patients in age categories up to the third decade, whereas ALK protein negative cases occur in older patients with an average age of 60 years. Both subgroups of lymphomas are aggressive but ALK+ lymphomas react well to systemic treatment, and have a more favorable prognosis. Primary skin ALCLs belong to a group of T-cell lymphoproliferative diseases of the skin and have, in the majority of cases, a favorable course without generalization.

Anaplastic Lymphoma Kinase↗
PubMed2005

Biological role of anaplastic lymphoma kinase in neuroblastoma.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor originally identified as part of the chimeric nucleophosmin-ALK protein in the t(2;5) chromosomal rearrangement associated with anaplastic large cell lymphoma. We recently demonstrated that the ALK kinase is constitutively activated by gene amplification at the ALK locus in several neuroblastoma cell lines. Forming a stable complex with hyperphosphorylated ShcC, activated ALK modifies the responsiveness of the mitogen-activated protein kinase pathway to growth factors. In the present study, the biological role of activated ALK was examined by suppressing the expression of ALK kinase in neuroblastoma cell lines using an RNA interference technique. The suppression of activated ALK in neuroblastoma cells by RNA interference significantly reduced the phosphorylation of ShcC, mitogen-activated protein kinases, and Akt, inducing rapid apoptosis in the cells. By immunohistochemical analysis, the cytoplasmic expression of ALK was detected in most of the samples of neuroblastoma tissues regardless of the stage of the tumor, whereas significant amplification of ALK was observed in only 1 of 85 cases of human neuroblastoma samples. These data demonstrate the limited frequency of ALK activation in the real progression of neuroblastoma.

Anaplastic Lymphoma Kinase↗
PubMed2001

ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is an uncommon tumor of extrapulmonary and pulmonary tissues with an unpredictable clinical course, occasional recurrences, and rare malignant transformation. Clonal abnormalities with rearrangements of chromosome of 2p23 and the ALK gene have been reported in a few cases. The purpose of this study is to investigate whether these are consistent abnormalities among IMTs or represent a distinct subset. DESIGN: Formalin-fixed, paraffin-embedded archival tissue sections from 47 IMTs in 40 patients were immunostained with monoclonal antibodies against ALK and p80. Fluorescence in situ hybridization for ALK rearrangements was done on 22 IMTs from 19 patients. Findings were correlated with clinical features and outcome. RESULTS: ALK positivity was observed in 17 of 47 IMTs (36%) and p80 positivity in 16 of 47 IMTs (34%). Fluorescence in situ hybridization showed ALK rearrangements in nine cases (47%), aneuploidy in three cases (16%), and no rearrangement in seven cases (37%). IMTs with ALK abnormalities by immunohistochemistry and/or fluorescence in situ hybridization originated in the abdomen/pelvis/retroperitoneum, chest, and extremities. The mean age was 6.6 years, with a male/female ratio of 1.3. 64% of patients had no evidence of disease at last follow-up, 45% had one or more recurrences, and 18% displayed histologic evidence of malignant transformation. The IMTs without ALK abnormalities occurred in older children, were more frequent in females, and had fewer recurrences. However, in this group of 40 patients, the differences between the groups with and without ALK abnormalities did not have statistical significance. Aneuploidy without ALK abnormalities was associated with malignant transformation in three of five cases. CONCLUSIONS: Abnormalities of ALK and p80 and evidence of chromosomal rearrangements of 2p23 occur in a significant proportion of IMTs. These changes are most frequent in abdominal and pulmonary IMTs in the first decade of life and are associated with a higher frequency of recurrence. These findings confirm the neoplastic nature of a subset IMT with ALK abnormalities and suggest that aneuploid IMT is a subset with more aggressive clinical behavior.

Adolescent↗
PubMed2006

Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase.

Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase in the insulin receptor superfamily. We recently demonstrated that the growth factors pleiotrophin (PTN) and midkine (MK) are ligands for ALK and that upon ALK activation, insulin receptor substrate-1 (IRS-1) and other substrates are phosphorylated. Here, the role of IRS-1 in ligand-mediated ALK signaling is investigated in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. These cells do not express ALK and IRS family members, and do not respond to exogenously added PTN or MK. We show that expression of ALK plus IRS-1 renders these cells independent of IL-3 owing to the activation of ALK by endogenous MK. Mutational analysis reveals that this transformed phenotype of 32D cells requires kinase-active ALK as well as the interaction of ALK with IRS-1. Furthermore, 32D/IRS-1/ALK cells display an enhanced activation of mitogen-activated protein kinase and PI3-kinase pathways, and a selective transcriptional activation of nuclear factor (NF)-kappaB. Small interfering RNA-mediated knockdown of the endogenous MK or p65/NF-kappaB revealed that both these are rate limiting for the transformed phenotype induced by ALK plus IRS-1. We conclude that the recruitment of IRS-1 to activated ALK and the activation of NF-kappaB are essential for the autocrine growth and survival signaling of MK.

Anaplastic Lymphoma Kinase↗
PubMed2003

Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA).

Anaplastic large-cell lymphoma is a subtype of non-Hodgkin lymphomas characterized by the expression of CD30. More than half of these lymphomas carry a chromosomal translocation t(2;5) leading to expression of the oncogenic tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK is capable of transforming fibroblasts and lymphocytes in vitro and of causing lymphomas in mice. Previously, we and others demonstrated phospholipase C-gamma and phosphatidylinositol 3-kinase as crucial downstream signaling mediators of NPM-ALK-induced oncogenicity. In this study, we used an ALK fusion protein as bait in a yeast two-hybrid screen identifying NIPA (nuclear interacting partner of ALK) as a novel downstream target of NPM-ALK. NIPA encodes a 60-kDa protein that is expressed in a broad range of human tissues and contains a classical nuclear translocation signal in its C terminus, which directs its nuclear localization. NIPA interacts with NPM-ALK and other ALK fusions in a tyrosine kinase-dependent manner and is phosphorylated in NPM-ALK-expressing cells on tyrosine and serine residues with serine 354 as a major phosphorylation site. Overexpression of NIPA in Ba/F3 cells was able to protect from apoptosis induced by IL-3 withdrawal. Mutations of the nuclear translocation signal or the Ser-354 phosphorylation site impaired the antiapoptotic function of NIPA. In NPM-ALK-transformed Ba/F3 cells, apoptosis triggered by wortmannin treatment was enhanced by overexpression of putative dominant-negative NIPA mutants. These results implicate an antiapoptotic role for NIPA in NPM-ALK-mediated signaling events.

Active Transport, Cell Nucleus↗