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NPM-ALK: a Driver of Lymphoma Pathogenesis and a Therapeutic Target

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cancers Review NPM-ALK: A Driver of Lymphoma Pathogenesis and a Therapeutic Target Elissa Andraos 1,2,3, Joséphine Dignac 1,2,3 and Fabienne Meggetto 1,2,3,4,5,*,†,‡ 1 Inserm, UMR1037 CRCT, F-31000 Toulouse, France; [email protected] (E.A.); [email protected] (J.D.) 2 Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France 3 CNRS, ERL5294 CRCT, F-31000 Toulouse, France 4 Institut Carnot Lymphome-CALYM, F-31024 Toulouse, France 5 Laboratoire d’Excellence Toulouse Cancer-TOUCAN, F-31024 Toulouse, France * Correspondence: [email protected]; Tel.: +33-(5)62-74-45-39; Fax: +33-(5)62-74-45-58 † The author joint European Research Initiative on ALK-related malignancies (ERIA) (http://www.erialcl.net/). ‡ The author belongs to Equipe Labellisée LIGUE 2017. Simple Summary: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase associated with Anaplas- tic Large Cell lymphoma (ALCL) through oncogenic translocations mainly NPM-ALK. Chemotherapy is effective in ALK(+) ALCL patients and induces remission rates of approximately 80%. The re- maining patients do not respond to chemotherapy and some patients have drug-resistant relapses. Different classes of ALK tyrosine kinase inhibitors (TKI) are available but used exclusively for EML4- ALK (+) lung cancers. The significant toxicities of most ALK inhibitors explain the delay in their use in pediatric ALCL patients. Some ALCL patients do not respond to the first generation TKI or develop an acquired resistance. Combination therapy with ALK inhibitors in ALCL is the current challenge. Abstract: Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lym- phoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, Citation: Andraos, E.; Dignac, J.; mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK Meggetto, F. NPM-ALK: A Driver of Lymphoma Pathogenesis and a translocations as it leads to remission rates of approximately 80%. However, the remaining patients Therapeutic Target. Cancers 2021, 13, do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore 144. https://doi.org/10.3390/ crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine cancers13010144 kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who Received: 10 November 2020 are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first Accepted: 23 December 2020 generation TKI, or develop an acquired resistance months following an initial response. Combination Published: 5 January 2021 therapy with ALK inhibitors in ALCL is the current challenge. Publisher’s Note: MDPI stays neu- Keywords: lymphoma; anaplastic large cell lymphoma; tyrosine kinase; anaplastic lymphoma kinase; tral with regard to jurisdictional clai- chemotherapy; target therapy; drug resistance ms in published maps and institutio- nal affiliations. 1. Introduction Copyright: © 2021 by the authors. Li- In 1994, the anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, was ini- censee MDPI, Basel, Switzerland. tially identified by Steve Morris through its involvement in the t(2;5)(p23;q35) chromosomal This article is an open access article translocation associated with anaplastic large cell lymphoma (ALCL), a subset of T-cell distributed under the terms and con- lymphomas [1]. This fusion combines the cytoplasmic domain of ALK to the N-terminus ditions of the Creative Commons At- of nucleolar phosphoprotein 1 (NPM1). Three years later, in 1997, the full-length human tribution (CC BY) license (https:// anaplastic lymphoma kinase (ALK) receptor or CD246 was entirely sequenced [2]. Al- creativecommons.org/licenses/by/ though its normal physiological role is not entirely clear, ALK seems to play a role in the 4.0/). Cancers 2021, 13, 144. https://doi.org/10.3390/cancers13010144 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 18 Cancers 2021, 13, 144 the development of the nervous system based on its high level of expression in embryonic2 of 17 neural tissue. The full-length ALK cDNA was originally cloned from the Rh30 rhabdomyosarcoma celldevelopment line and its of expression the nervous has systembeen confirmed based on in its the high alveolar level subtype of expression of primary in embryonic rhabdo- myosarcomaneural tissue. [3]. TheThe human full-length ALK ALK gene cDNA is located was originallyat the chromosome cloned from region the Rh302p23. rhabdomyosarcoma2–p23.1, contains 26 cell line and its expression has been confirmed in the alveolar subtype of primary rhab- exons and encodes the full-length ALK protein which includes 1620 amino acids and domyosarcoma [3]. weighs 180 kDa. N-linked glycosylation is a highly regulated post-translational modifica- The human ALK gene is located at the chromosome region 2p23.2–p23.1, contains 26 tion, which is involved in several biological processes such as protein folding and confor- exons and encodes the full-length ALK protein which includes 1620 amino acids and weighs mation, oligomerization, sorting, cell cell interactions, and targeting of proteins to sub or 180 kDa. N-linked glycosylation is- a highly regulated post-translational modification,- extrawhich-cellular is involved locations in several. As a biologicalresult of the processes 16 N-glycosylation such as protein sites folding in ALK, and the conformation, molecular weightoligomerization, of the full-length sorting, ALK cell-cell is of interactions,approximately and 220 targeting kDa [4]. of proteins to sub- or extra- cellularALK locations. is an enzyme As a resultwith tyrosine of the 16 kinase N-glycosylation activity (Figure sites in1), ALK, which the catalyses molecular the weight trans- ferenceof the full-length of a gamma ALK-phosphate is of approximately group from 220 adenosine kDa [4]. triphosphate (ATP) to a tyrosine residueALK on is a ansubstrate enzyme protein with tyrosine. One member kinase activity of the (Figurereceptor1), tyrosine which catalyses kinase the(RTK) transfer- ALK familyence of contains a gamma-phosphate three parts: an group extra from-cellular adenosine ligand triphosphate-binding domain (ATP) (ECD), to a tyrosine a single residue mem- braneon a substrate-spanning protein.domain Oneand an member intracellular of the receptorcytoplasmic tyrosine catalytic kinase domain (RTK) (ICD) ALK. Whilst family thecontains tyrosine three kinase parts: domain an extra-cellular of human ALK ligand-binding shares a high domain degree (ECD), of similarity a single with membrane- that of thespanning insulin domainreceptor and(IR), an its intracellularextracellular cytoplasmicdomain is unique catalytic among domain the RTK (ICD). family Whilst in con- the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the taining two MAM domains (meprin, A5 protein, and receptor protein tyrosine phospha- insulin receptor (IR), its extracellular domain is unique among the RTK family in containing tase mu), an LDLa domain (low-density lipoprotein receptor class A) and a glycine-rich two MAM domains (meprin, A5 protein, and receptor protein tyrosine phosphatase mu), region [1,5] Based on the overall homology of the ECD, ALK is closely related to the leu- an LDLa domain. (low-density lipoprotein receptor class A) and a glycine-rich region [1,5]. kocyteBased onreceptor the overall tyrosine homology kinase (LTK) of the which ECD, ALK also ishas closely a glycine related-rich to region the leukocyte in its ECD receptor. Thus, togethertyrosine with kinase the (LTK) insulin which receptor, also has ALK a glycine-rich forms a unique region subgroup in its ECD. in Thus,the IR together RTK super- with familythe insulin [4]. receptor, ALK forms a unique subgroup in the IR RTK superfamily [4]. FigureFigure 1. ALK proteinprotein structure. structure The. The intracellular intracellular tyrosine tyrosine kinase kinase domain domain harbors harbors the 3 tyrosinethe 3 motif Tyr1278, Tyr1282, Tyr1283, which represents the major auto-phosphorylation site regulating tyrosine motif Tyr1278, Tyr1282, Tyr1283, which represents the major auto-phosphoryla- kinase activity. tion site regulating kinase activity. During the embryonic development of chickens, mice, rats, and humans, the ALK expressionDuring profile the embryonic is restricted development to discrete areasof chickens, of the developing mice, rats, nervousand humans system, the and ALK the expressionALK expression profile level is restricted decreases to after discrete birth. areas ALK of has the also developing been identified nervous in system non-vertebrate and the ALKmodel expression organisms levelDrosophila decreases melanogaster after birth.and ALKCaenorhabditis has also been elegans identifiedwhere in non it is-vertebrate expressed modelat low organisms levels in theDrosophila nervous melanogaster system and and is proposedCaenorhabditis to inhibit elegans or where destabilize it is expressed synapse atdifferentiation. low levels in the While nervous the function(s) system and of is ALK proposed is not specificallyto inhibit or addressed, destabilize its synapse conserved dif- ferentiationexpression. within While thethe CNSfunction(s) suggests of anALK important is not specifically role(s) in neuraladdressed, development its conserved [6]. ex- pressionSeveral within putative
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  • "The Genecards Suite: from Gene Data Mining to Disease Genome Sequence Analyses". In: Current Protocols in Bioinformat

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    The GeneCards Suite: From Gene Data UNIT 1.30 Mining to Disease Genome Sequence Analyses Gil Stelzer,1,5 Naomi Rosen,1,5 Inbar Plaschkes,1,2 Shahar Zimmerman,1 Michal Twik,1 Simon Fishilevich,1 Tsippi Iny Stein,1 Ron Nudel,1 Iris Lieder,2 Yaron Mazor,2 Sergey Kaplan,2 Dvir Dahary,2,4 David Warshawsky,3 Yaron Guan-Golan,3 Asher Kohn,3 Noa Rappaport,1 Marilyn Safran,1 and Doron Lancet1,6 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 2LifeMap Sciences Ltd., Tel Aviv, Israel 3LifeMap Sciences Inc., Marshfield, Massachusetts 4Toldot Genetics Ltd., Hod Hasharon, Israel 5These authors contributed equally to the paper 6Corresponding author GeneCards, the human gene compendium, enables researchers to effectively navigate and inter-relate the wide universe of human genes, diseases, variants, proteins, cells, and biological pathways. Our recently launched Version 4 has a revamped infrastructure facilitating faster data updates, better-targeted data queries, and friendlier user experience. It also provides a stronger foundation for the GeneCards suite of companion databases and analysis tools. Improved data unification includes gene-disease links via MalaCards and merged biological pathways via PathCards, as well as drug information and proteome expression. VarElect, another suite member, is a phenotype prioritizer for next-generation sequencing, leveraging the GeneCards and MalaCards knowledgebase. It au- tomatically infers direct and indirect scored associations between hundreds or even thousands of variant-containing genes and disease phenotype terms. Var- Elect’s capabilities, either independently or within TGex, our comprehensive variant analysis pipeline, help prepare for the challenge of clinical projects that involve thousands of exome/genome NGS analyses.