Other entities represented in this entry:
HGNC Approved Gene Symbol: ALK
Cytogenetic location: 2p23.2-p23.1 Genomic coordinates (GRCh38): 2:29,192,774-29,921,586 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.2-p23.1 | {Neuroblastoma, susceptibility to, 3} | 613014 | 3 |
The ALK gene encodes a receptor tyrosine kinase that plays a role in regulation of Wnt/beta-catenin (see 116806) signaling and is involved in the development of many cancer types, especially non-small-cell lung cancer (NSCLC) (summary by Majumder et al., 2021).
Large-cell lymphomas comprise approximately 25% of all non-Hodgkin lymphomas in children and young adults, and approximately one-third of these tumors have a t(2;5)(p23;q35) translocation. By a positional cloning strategy, Morris et al. (1994) demonstrated that the rearrangement fused the nucleophosmin gene (NPM1; 164040), located on 5q35, to a previously unidentified protein tyrosine kinase gene, which they called anaplastic lymphoma kinase (ALK), located on 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin is linked to the catalytic domain of ALK. Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases (see INSR; 147670). Unscheduled expression of the truncated ALK was thought to contribute to malignant transformation in these lymphomas.
Benharroch et al. (1998) studied the morphologic and phenotypic spectrum of 123 cases of lymphoma, all of which expressed ALK protein. They provided strong evidence that the morphologic patterns of anaplastic large-cell lymphoma (ALCL), described in previous reports as representing possible subtypes of ALCL, are in fact morphologic variants of the same disease entity. They concluded that ALK-positive neoplasms represent a distinct entity. Because the morphology of the tumors is often neither anaplastic nor large cell, the authors suggested that the tumors should be referred to as ALK lymphomas.
The secreted protein 'Jelly belly' (Jeb) is required for an essential signaling event in Drosophila muscle development. In the absence of functional Jeb, visceral muscle precursors are normally specified but fail to migrate and differentiate. Lee et al. (2003) demonstrated that the Jeb receptor is the Drosophila homolog of ALK. In Drosophila, localized Jeb activates Alk and the downstream Ras/mitogen-activated protein kinase cascade to specify a select group of visceral muscle precursors as muscle-patterning pioneers. Jeb/Alk signaling induces the myoblast fusion gene 'dumbfounded' (duf; also known as kirre; see 607761) as well as org1, a Drosophila homolog of mammalian TBX1 (602054), in these cells.
Englund et al. (2003) also showed that Drosophila Alk is the receptor for Jeb in the developing visceral mesoderm and that Jeb binding stimulates an Alk-driven extracellular signal-regulated kinase-mediated signaling pathway, which results in the expression of the downstream gene duf, which is needed for muscle fusion. This new signal transduction pathway drives specification of the muscle founder cells, and the regulation of duf expression by Drosophila Alk/RTK explains the visceral-mesoderm-specific muscle fusion defects observed in both Alk and Jeb mutant animals.
By expression profiling of ALK-positive ALCLs, Piva et al. (2006) identified a large group of ALK-regulated genes. Functional RNA interference screening on a set of these transcriptional targets revealed that CEBPB (189965) and BCL2A1 (601056) were absolutely necessary to induce cell transformation and/or to sustain growth and survival of ALK-positive ALCL cells.
IL22R1 (605457) is not expressed on normal leukocytes, but it is expressed on T-cells from ALK-positive ALCL patients. Savan et al. (2011) found that mice expressing a human IL22R1 transgene on lymphocytes exhibited deterioration of health at 8 to 12 weeks of age and death due to multiorgan inflammation. Transgenic mice developed neutrophilia that correlated with increased circulating Il17 (IL17A; 603149) and Gcsf (CSF3; 138970), as well as increased serum Il22 (605330). ALK-positive ALCL patients had elevated IL22, IL17, and IL8 (146930) before treatment, but those in complete remission after chemotherapy did not have detectable IL22 and IL17. Savan et al. (2011) concluded that IL22R1 and IL22 are involved in inflammation and ALK-positive ALCL.
By reciprocal immunoprecipitation of transfected 293T cells, Takagi et al. (2013) found that the adaptor protein SHF (617313) interacted with ALK. In neuroblastoma cells and patient tissue, ALK and SHF showed an inverse relationship, with high ALK and low SHF mRNA associated with poor prognosis. Overexpression of ALK and knockdown of SHF via short interfering RNA yielded similar and additive results, including increased growth, ALK phosphorylation, and activation of ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and STAT3 (102582). Knockdown of SHF also increased mobility and invasiveness of neuroblastoma cells. Takagi et al. (2013) concluded that SHF negatively regulates ALK signal transduction.
Wiesner et al. (2015) reported a novel isoform of ALK that is expressed in approximately 11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19 and is termed ALK(ATI). In ALK(ATI)-expressing tumors, the ATI site is enriched for H3K4 trimethylation and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes 3 proteins with molecular masses of 61.1, 60.8, and 58.7 kD, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signaling pathways, drives growth factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumors may benefit from ALK inhibitors.
By Western blot analysis, Majumder et al. (2021) showed that levels of GRB2 (108355) and NOX4 (605261) were elevated in tissues from mouse models for Alzheimer disease (AD; see 104300) and type 2 diabetes (T2D; 125853), as well as in tissues from AD and T2D patients. Knockdown analysis in SHSY-5Y and HepG2 cells revealed that miRNA1271 targeted and restricted expression of ALK and RYK (600524), which elevated expression of GRB2 and NOX4. Moreover, PAX4 (167413), a transcription factor for both GRB2 and NOX4, was overexpressed during ALK and RYK knockdown due to reduced expression of the PAX4 suppressor ARX (300382) via beta-catenin (see 116806) signaling. In addition, expression of various cytoskeletal proteins was downregulated in liver tissue of T2D patients and in ALK/RYK knockdown cells, but overexpression of GRB2 reversed the cytoskeletal degradation through interaction with NOX4.
ALK/EML4 Fusion Protein
Soda et al. (2007) showed that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the EML4 gene (607442) and the ALK gene in non-small-cell lung cancer (211980) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumors in nude mice. Soda et al. (2007) detected the ALK-EML4 fusion transcript in 5 of 75 (6.7%) Japanese patients with non-small-cell lung cancer patients examined; none of these patients had a mutation in the epidermal growth factor receptor gene (EGFR; 131550). The fusion gene encoded a deduced 1,059-amino acid protein with an N-terminal portion (residues 1-496) identical to that of human EML4 and a C-terminal portion (residues 497-1059) identical to the intracellular domain (residues 1058-1620) of human ALK.
The EML4-ALK fusion type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers. Choi et al. (2010) reported the discovery of 2 secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to 2 different ALK inhibitors.
ALK/NPM1 Fusion Protein
Zhang et al. (2007) stated that ALK tyrosine kinase expression is normally confined to neural cells, but chromosomal translocations involving ALK and various partners, most frequently NPM1, result in ectopic expression of ALK in a subset of T-cell lymphomas (TCLs). The NPM1/ALK fusion protein contains the NPM1 oligomerization motif and the ALK catalytic domain, is constitutively activated through autophosphorylation, and mediates malignant cell transformation in vitro and in vivo by activating downstream effectors, including STAT3 (102582). Zhang et al. (2007) found that TCL cell lines expressing NPM1/ALK expressed STAT5B (604260), but not STAT5A (601511), protein, whereas normal resting and activated T cells from peripheral blood and ALK-negative TCL cell lines expressed STAT5A protein. Activated NPM1/ALK-positive TCL cell lines also did not express STAT5A mRNA, in spite of having an intact STAT5A gene. Analysis of the CpG island in the STAT5A promoter showed that the region was methylated in NPM1/ALK-positive, but not NPM1/ALK-negative, T cells. Chromatin immunoprecipitation analysis revealed that SP1 (189906) bound the STAT5A promoter in normal activated T cells, whereas MECP2 (300005) bound the promoter of NPM1/ALK-positive TCL cells. Demethylation of the promoter resulted in STAT5A activation and inhibition of NPM1/ALK expression by binding of STAT5A to the NPM1/ALK fusion gene. Expression of NPM1/ALK in NPM1/ALK-negative TCL cells resulted in silencing of STAT5A in a STAT3-dependent manner, whereas small interfering RNA mediated-depletion of NPM1/ALK resulted in STAT5A expression. Zhang et al. (2007) concluded that NPM1/ALK induces epigenetic silencing of the STAT5A gene and that the STAT5A protein can act as a tumor suppressor by inhibiting NPM1/ALK expression.
Mosse et al. (2008) stated that the ALK gene comprises 29 coding exons.
Morris et al. (1994) identified the ALK gene on chromosome 2p23 by positional cloning using a t(2;5)(p23;q35) translocation. Mathew et al. (1995) mapped the mouse homolog to chromosome 17 by interspecific backcross analysis, thus confirming the homology between the portion of distal mouse 17 and the short arm of human chromosome 2.
In 2 patients with ALK-positive anaplastic large-cell lymphoma (ALCL) and a third patient with ALK-negative inflammatory myofibroblastic tumors (IMT), Cools et al. (2002) identified novel rearrangements involving the ALK gene. One ALCL patient had a t(2;17)(p23;q25) that resulted in fusion of exons of the ALO17 gene (RNF213; 613768) to exons of the ALK gene. The other ALCL patient had an unknown karyotype that led to fusion of exons of the CLTC gene (118955) to exons of the ALK gene. The IMT patient had a t(2;11;2)(p23;p15;q31) that resulted in fusion of exons of the CARS gene (123859) to exons of the ALK gene. The predicted fusion proteins contain 1,172 N-terminal amino acids of ALO17, 1,634 N-terminal amino acids of CLTC, or 606 N-terminal amino acids of CARS fused in frame to the same 562 amino acids of ALK, including the ALK kinase domain.
Mosse et al. (2008) identified 3 separate germline missense mutations in the tyrosine kinase domain of the ALK gene (105590.0001-105590.0003) that segregated with the disease in 8 separate families with neuroblastoma (NBLST3; 613014). There was incomplete penetrance. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of the samples. Nine of the 10 mutations mapped to critical regions of the kinase domain and were predicted with high probability to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK mRNA resulted in profound inhibition of growth in all cell lines harboring mutant or amplified ALK, as well as in 2 of 6 wildtype cell lines for ALK. Mosse et al. (2008) concluded that heritable mutations of ALK are the main cause of susceptibility to the development of neuroblastoma within families.
Janoueix-Lerosey et al. (2008) conducted a genomewide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the ALK tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumor DNAs, they identified somatic mutations of the ALK kinase domain that mainly clustered in 2 hotspots. Germline mutations were observed in 2 neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated, and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wildtype ALK, led to a marked decrease of cell proliferation. Altogether, Janoueix-Lerosey et al. (2008) concluded that their data identified ALK as critical player in neuroblastoma development that may represent a therapeutic target.
In a genomewide scan of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, Chen et al. (2008) identified the ALK locus as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed 8 novel missense mutations in 13 of 215 (6.1%) fresh tumors and 8 of 24 (33%) neuroblastoma-derived cell lines. All but 1 mutation in the primary samples (12 of 13) were found in stage 3 or 4 of the disease and were harbored in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wildtype kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumors in nude mice. Furthermore, Chen et al. (2008) demonstrated that downregulation of ALK through RNA interference suppressed proliferation of neuroblastoma cells harboring mutated ALK.
George et al. (2008) reported the detection of mutations in the ALK gene (see, e.g., 105590.0001 and 105590.0004) in 8% of primary neuroblastomas. Five were identified in the kinase domain of ALK, of which 3 were somatic and 2 were germline. The most frequent mutation, F1174L, was identified in 3 different neuroblastoma cell lines as well as in several tumor samples. It was not identified in any germline cases, consistent with it being a somatic mutation. ALK cDNAs encoding the F1174L and R1275Q (105590.0001) variants, but not wildtype ALK cDNA, transformed interleukin-3 (IL3; 147740)-dependent murine hematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to a small-molecule inhibitor of ALK. Furthermore, 2 human neuroblastoma cell lines harboring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis. Short hairpin RNA-mediated knockdown of ALK expression also resulted in apoptosis and impaired cell proliferation. Thus, George et al. (2008) concluded that activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumors and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibitors.
Mosse et al. (2008), Janoueix-Lerosey et al. (2008), Chen et al. (2008), and George et al. (2008) all found somatic missense mutations at codon F1174, within the kinase domain.
To determine the frequency of ALK mutations in neuroblastic tumors, Bourdeaut et al. (2012) sequenced the ALK gene in 26 patients with perinatal onset of neuroblastoma, 16 patients with multifocal postnatal onset of neuroblastoma, and 8 children or young adults with multiple malignancies, including a neuroblastic tumor. A de novo heterozygous germline mutation (R1275Q; 105590.0001) was found in 1 patient with perinatal onset, and 2 different heterozygous mutations (see, e.g., 105590.0003) were found in 2 unrelated patients with postnatal multifocal onset. However, each of the latter 2 mutations were found in several unaffected relatives, indicating incomplete penetrance. Tumor tissue from all 3 patients also carried the corresponding mutation. Considering the whole cohort, younger age at onset did not seem to offer selection criteria for ALK analysis, but all mutation carriers had multifocal tumors. Bourdeaut et al. (2012) concluded that ALK mutations are rare events in patients with a high probability of predisposition to neuroblastoma.
Chiarle et al. (2008) vaccinated BALB/c mice with DNA plasmids encoding portions of the cytoplasmic domain of ALK and observed potent and long-lasting protection from local and systemic lymphoma growth. The vaccination elicited ALK-specific interferon-gamma (147570) responses and CD8+ T cell-mediated cytotoxicity. A combination of chemotherapy and vaccination significantly enhanced the survival of mice challenged with ALK+ lymphomas.
EML4-ALK Fusion Gene
Maddalo et al. (2014) described an efficient method to induce specific chromosomal rearrangements in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals, applying it to generate a mouse model of EML4 (607442)-ALK-driven lung cancer. The resulting tumors invariably harbored the Eml4-Alk inversion; expressed the Eml4-Alk fusion gene; displayed histopathologic and molecular features typical of ALK-positive human nonsmall cell lung cancers (NSCLCs); and responded to treatment with ALK inhibitors. Maddalo et al. (2014) suggested that this general strategy substantially expands the ability to model human cancers in mice and potentially in other organisms.
In 5 independent families segregating neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a 3824G-A transition in the ALK gene, resulting in an arg1275-to-gln (R1275Q) substitution. The mutation manifested incomplete penetrance but was not identified in 218 normal control chromosomes. The mutation occurs in the kinase activation loop of the protein and has a 91% probability of being an activating mutation. In 1 family an unaffected mutation-carrying mother transmitted the mutation to 3 offspring by 3 different fathers; each of these 3 offspring developed neuroblastoma.
Janoueix-Lerosey et al. (2008) identified 1 family in which an unaffected mutation-carrying mother transmitted the mutation to 2 affected offspring, each by a different father.
George et al. (2008) identified this mutation in a patient with neuroblastoma.
Chen et al. (2008) identified the R1275Q substitution as a somatic mutation in several neuroblastoma tumor samples.
Bourdeaut et al. (2012) identified a de novo heterozygous germline R1275Q mutation in a patient with perinatal onset of multifocal neuroblastoma. The mutation was also found in several tumors.
In a large 3-generation pedigree segregating familial neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a G-to-C transversion at nucleotide 3383 in the ALK gene, resulting in a glycine-to-alanine substitution at codon 1128 (G1128A). Five individuals with the mutation developed neuroblastoma, but several carriers did not, indicating incomplete penetrance. This mutation occurred in the P loop of the protein and was considered to have 95% probability of being an activating mutation. This mutation was not identified in 218 normal control alleles.
In 2 families segregating neuroblastoma (NBLST3; 613014), Mosse et al. (2008) identified a G-to-C transversion at nucleotide 3575 of the ALK gene, resulting in an arginine-to-proline substitution at codon 1192 (R1192P). This mutation manifested incomplete penetrance. The mutation occurred in the beta-4 strand of the protein and was predicted with 96% probability to be an activating mutation. The mutation was not identified in 218 control chromosomes.
Janoueix-Lerosey et al. (2008) independently identified a family segregating neuroblastoma and carrying the R1192P allele. In this 3-generation pedigree, the grandmother was unaffected. The daughter developed a ganglioneuroblastoma at 12 years of age, and 2 grandchildren developed stage 4 neuroblastomas at 3 and 4 months of age, respectively. In addition to the grandmother, the parents of the affected grandchildren were also unaffected.
Bourdeaut et al. (2012) identified a heterozygous germline R1192P mutation in a child who developed neuroblastoma at age 6 months and later developed multiple ganglioneuromas in various places up to age 6 years. The mutation was found in all tumors tested. However, this germline mutation was also found in 3 unaffected family members, including the patient's mother, indicating incomplete penetrance.
In a patient with neuroblastoma (NBLST3; 613014), George et al. (2008) identified a 3452C-T transition in the ALK gene, resulting in a threonine-to-methionine substitution at codon 1151 (T1151M) in the kinase domain of ALK.
Benharroch, D., Meguerian-Bedoyan, Z., Lamant, L., Amin, C., Brugieres, L., Terrier-Lacombe, M.-J., Haralambieva, E., Pulford, K., Pileri, S., Morris, S. W., Mason, D. Y., Delsol, G. ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood 91: 2076-2084, 1998. [PubMed: 9490693]
Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others. ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome. Europ. J. Hum. Genet. 20: 291-297, 2012. [PubMed: 22071890] [Full Text: https://doi.org/10.1038/ejhg.2011.195]
Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455: 971-974, 2008. [PubMed: 18923524] [Full Text: https://doi.org/10.1038/nature07399]
Chiarle, R., Martinengo, C., Mastini, C., Ambrogio, C., D'Escamard, V., Forni, G., Inghirami, G. The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination. Nature Med. 14: 676-680, 2008. [PubMed: 18469826] [Full Text: https://doi.org/10.1038/nm1769]
Choi, Y. L., Soda, M., Yamashita, Y., Ueno, T., Takashima, J., Nakajima, T., Yatabe, Y., Takeuchi, K., Hamada, T., Haruta, H., Ishikawa, Y., Kimura, H., Mitsudomi, T., Tanio, Y., Mano, H. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. New Eng. J. Med. 363: 1734-1739, 2010. [PubMed: 20979473] [Full Text: https://doi.org/10.1056/NEJMoa1007478]
Cools, J., Wlodarska, I., Somers, R., Mentens, N., Pedeutour, F., Maes, B., De Wolf-Peeters, C., Pauwels, P., Hagemeijer, A., Marynen, P. Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 34: 354-362, 2002. [PubMed: 12112524] [Full Text: https://doi.org/10.1002/gcc.10033]
Englund, C., Loren, C. E., Grabbe, C., Varshney, G. K., Deleuil, F., Hallberg, B., Palmer, R. H. Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion. Nature 425: 512-516, 2003. [PubMed: 14523447] [Full Text: https://doi.org/10.1038/nature01950]
George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455: 975-978, 2008. [PubMed: 18923525] [Full Text: https://doi.org/10.1038/nature07397]
Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455: 967-970, 2008. [PubMed: 18923523] [Full Text: https://doi.org/10.1038/nature07398]
Lee, H.-H., Norris, A., Weiss, J. B., Frasch, M. Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers. Nature 425: 507-512, 2003. [PubMed: 14523446] [Full Text: https://doi.org/10.1038/nature01916]
Maddalo, D., Manchado, E., Concepcion, C. P., Bonetti, C., Vidigal, J. A., Han, Y.-C., Ogrodowski, P., Crippa, A., Rekhtman, N., de Stanchina, E., Lowe, S. W., Ventura, A. In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. Nature 516: 423-427, 2014. Note: Erratum: Nature 524: 502 only, 2015. [PubMed: 25337876] [Full Text: https://doi.org/10.1038/nature13902]
Majumder, P., Chanda, K., Das, D., Singh, B. K., Chakrabarti, P., Jana, N. R., Mukhopadhyay, D. A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's disease and type 2 diabetes. Biochem. J. 478: 3297-3317, 2021. [PubMed: 34409981] [Full Text: https://doi.org/10.1042/BCJ20210175]
Mathew, P., Morris, S. W., Kane, J. R., Shurtleff, S. A., Pasquini, M., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. Localization of the murine homolog of the anaplastic lymphoma kinase (Alk) gene on mouse chromosome 17. Cytogenet. Cell Genet. 70: 143-144, 1995. [PubMed: 7736780] [Full Text: https://doi.org/10.1159/000134080]
Morris, S. W., Kirstein, M. N., Valentine, M. B., Dittmer, K. G., Shapiro, D. N., Saltman, D. L., Look, A. T. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263: 1281-1284, 1994. Note: Erratum: Science 267: 316-317, 1995. [PubMed: 8122112] [Full Text: https://doi.org/10.1126/science.8122112]
Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455: 930-935, 2008. [PubMed: 18724359] [Full Text: https://doi.org/10.1038/nature07261]
Piva, R., Pellegrino, E., Mattioli, M., Agnelli, L., Lombardi, L., Boccalatte, F., Costa, G., Ruggeri, B. A., Cheng, M., Chiarle, R., Palestro, G., Neri, A., Inghirami, G. Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes. J. Clin. Invest. 116: 3171-3182, 2006. [PubMed: 17111047] [Full Text: https://doi.org/10.1172/JCI29401]
Savan, R., McFarland, A. P., Reynolds, D. A., Feigenbaum, L., Ramakrishnan, K., Karwan, M., Shirota, H., Klinman, D. M., Dunleavy, K., Pittaluga, S., Anderson, S. K., Donnelly, R. P., Wilson, W. H., Young, H. A. A novel role for IL-22R1 as a driver of inflammation. Blood 117: 575-584, 2011. [PubMed: 20971950] [Full Text: https://doi.org/10.1182/blood-2010-05-285908]
Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Hatanaka, H., Bando, M., Ohno, S., Ishikawa, Y., Aburatani, H., Niki, T., Sohara, Y., Sugiyama, Y., Mano, H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448: 561-566, 2007. [PubMed: 17625570] [Full Text: https://doi.org/10.1038/nature05945]
Takagi, D., Tatsumi, Y., Yokochi, T., Takatori, A., Ohira, M., Kamijo, T., Kondo, S., Fujii, Y., Nakagawara, A. Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma. Cancer Sci. 104: 563-572, 2013. [PubMed: 23360421] [Full Text: https://doi.org/10.1111/cas.12115]
Wiesner, T., Lee, W., Obenauf, A. C., Ran, L., Murali, R., Zhang, Q. F., Wong, E. W. P., Hu, W., Scott, S. N., Shah, R. H., Landa, I., Button, J., and 20 others. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature 526: 453-457, 2015. [PubMed: 26444240] [Full Text: https://doi.org/10.1038/nature15258]
Zhang, Q., Wang, H. Y., Liu, X., Wasik, M. A. STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nature Med. 13: 1341-1348, 2007. [PubMed: 17922009] [Full Text: https://doi.org/10.1038/nm1659]