Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies.

Central European Institute of Technology Masaryk University Kamenice 5 62500 Brno Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno 62500 Brno Czech Republic

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Niida H., Nakanishi M. DNA damage checkpoints in mammals. Mutagenesis. 2006;21:3–9. doi: 10.1093/mutage/gei063. PubMed DOI

Skorski T. Oncogenic tyrosine kinases and the DNA-damage response. Nat. Rev. Cancer. 2002;2:351–360. doi: 10.1038/nrc799. PubMed DOI

Deutsch E., Dugray A., AbdulKarim B., Marangoni E., Maggiorella L., Vaganay S., M’Kacher R., Rasy S.D., Eschwege F., Vainchenker W., et al. BCR-ABL down-regulates the DNA repair protein DNA-PKcs. Blood. 2001;97:2084–2090. doi: 10.1182/blood.V97.7.2084. PubMed DOI

Faderl S., Talpaz M., Estrov Z., O’Brien S., Kurzrock R., Kantarjian H.M. The biology of chronic myeloid leukemia. N. Engl. J. Med. 1999;341:164–172. doi: 10.1056/NEJM199907153410306. PubMed DOI

Benz-Lemoine E., Brizard A., Huret J.L., Babin P., Guilhot F., Couet D., Tanzer J. Malignant histiocytosis: A specific t(2;5)(p23;q35) translocation? Review of the literature. Blood. 1988;72:1045–1047. PubMed

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. 1994;263:1281–1284. doi: 10.1126/science.8122112. PubMed DOI

Mano H. Alkoma: A cancer subtype with a shared target. Cancer Discov. 2012;2:495–502. doi: 10.1158/2159-8290.CD-12-0009. PubMed DOI

Falini B., Pulford K., Pucciarini A., Carbone A., De Wolf-Peeters C., Cordell J., Fizzotti M., Santucci A., Pelicci P.G., Pileri S., et al. Lymphomas expressing ALK fusion protein(s) other than NPM-ALK. Blood. 1999;94:3509–3515. PubMed

Hernandez L., Bea S., Bellosillo B., Pinyol M., Falini B., Carbone A., Ott G., Rosenwald A., Fernandez A., Pulford K., et al. Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: Identification of a new TFG-ALK(XL) chimeric gene with transforming activity. Am. J. Pathol. 2002;160:1487–1494. doi: 10.1016/S0002-9440(10)62574-6. PubMed DOI PMC

Lamant L., Dastugue N., Pulford K., Delsol G., Mariame B. A new fusion gene tpm3-alk in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Blood. 1999;93:3088–3095. PubMed

Colleoni G.W., Bridge J.A., Garicochea B., Liu J., Filippa D.A., Ladanyi M. ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35) Am. J. Pathol. 2000;156:781–789. doi: 10.1016/S0002-9440(10)64945-0. PubMed DOI PMC

Zamo A., Chiarle R., Piva R., Howes J., Fan Y., Chilosi M., Levy D.E., Inghirami G. Anaplastic lymphoma kinase (ALK) activates STAT3 and protects hematopoietic cells from cell death. Oncogene. 2002;21:1038–1047. doi: 10.1038/sj.onc.1205152. PubMed DOI

Slupianek A., Nieborowska-Skorska M., Hoser G., Morrione A., Majewski M., Xue L., Morris S.W., Wasik M.A., Skorski T. Role of phosphatidylinositol 3-kinase-AKT pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res. 2001;61:2194–2199. PubMed

Bai R.Y., Dieter P., Peschel C., Morris S.W., Duyster J. Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase c-gamma to mediate its mitogenicity. Mol. Cell. Biol. 1998;18:6951–6961. doi: 10.1128/MCB.18.12.6951. PubMed DOI PMC

Chiarle R., Voena C., Ambrogio C., Piva R., Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat. Rev. Cancer. 2008;8:11–23. doi: 10.1038/nrc2291. PubMed DOI

Rouse J., Jackson S.P. Interfaces between the detection, signaling, and repair of DNA damage. Science. 2002;297:547–551. doi: 10.1126/science.1074740. PubMed DOI

Yang X.H., Zou L. Checkpoint and coordinated cellular responses to DNA damage. Results Probl. Cell Differ. 2006;42:65–92. PubMed

D’Amours D., Jackson S.P. The mre11 complex: At the crossroads of DNA repair and checkpoint signalling. Nat. Rev. Mol. Cell Biol. 2002;3:317–327. doi: 10.1038/nrm805. PubMed DOI

Lee J.H., Paull T.T. ATM activation by DNA double-strand breaks through the MRE11-RAD50-NBS1 complex. Science. 2005;308:551–554. doi: 10.1126/science.1108297. PubMed DOI

Byun T.S., Pacek M., Yee M.C., Walter J.C., Cimprich K.A. Functional uncoupling of mcm helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 2005;19:1040–1052. doi: 10.1101/gad.1301205. PubMed DOI PMC

Zou L., Elledge S.J. Sensing DNA damage through atrip recognition of RPA-ssDNA complexes. Science. 2003;300:1542–1548. doi: 10.1126/science.1083430. PubMed DOI

Bartek J., Lukas J. CHK1 and CHK2 kinases in checkpoint control and cancer. Cancer Cell. 2003;3:421–429. doi: 10.1016/S1535-6108(03)00110-7. PubMed DOI

Blackford A.N., Jackson S.P. Atm, atr, and DNA-PK: The trinity at the heart of the DNA damage response. Mol. Cell. 2017;66:801–817. doi: 10.1016/j.molcel.2017.05.015. PubMed DOI

Meulmeester E., Pereg Y., Shiloh Y., Jochemsen A.G. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle. 2005;4:1166–1170. doi: 10.4161/cc.4.9.1981. PubMed DOI

Stommel J.M., Wahl G.M. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J. 2004;23:1547–1556. doi: 10.1038/sj.emboj.7600145. PubMed DOI PMC

Meek D.W. Tumour suppression by p53: A role for the DNA damage response? Nat. Rev. Cancer. 2009;9:714–723. doi: 10.1038/nrc2716. PubMed DOI

Prives C., Hall P.A. The p53 pathway. J. Pathol. 1999;187:112–126. doi: 10.1002/(SICI)1096-9896(199901)187:1<112::AID-PATH250>3.0.CO;2-3. PubMed DOI

Joerger A.C., Fersht A.R. The tumor suppressor p53: From structures to drug discovery. Cold Spring Harb. Perspect. Biol. 2010;2:a000919. doi: 10.1101/cshperspect.a000919. PubMed DOI PMC

Herrero A.B., Rojas E.A., Misiewicz-Krzeminska I., Krzeminski P., Gutierrez N.C. Molecular mechanisms of p53 deregulation in cancer: An overview in multiple myeloma. Int. J. Mol. Sci. 2016;17:2003. doi: 10.3390/ijms17122003. PubMed DOI PMC

Bond G.L., Hu W., Bond E.E., Robins H., Lutzker S.G., Arva N.C., Bargonetti J., Bartel F., Taubert H., Wuerl P., et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591–602. doi: 10.1016/j.cell.2004.11.022. PubMed DOI

Toledo F., Wahl G.M. MDM2 and MDM4: p53 regulators as targets in anticancer therapy. Int. J. Biochem. Cell Biol. 2007;39:1476–1482. doi: 10.1016/j.biocel.2007.03.022. PubMed DOI PMC

Hu W., Feng Z., Ma L., Wagner J., Rice J.J., Stolovitzky G., Levine A.J. A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. Cancer Res. 2007;67:2757–2765. doi: 10.1158/0008-5472.CAN-06-2656. PubMed DOI

Whibley C., Pharoah P.D., Hollstein M. p53 polymorphisms: Cancer implications. Nat. Rev. Cancer. 2009;9:95–107. doi: 10.1038/nrc2584. PubMed DOI

Williams A.B., Schumacher B. p53 in the DNA-damage-repair process. Cold Spring Harb. Perspect. Med. 2016;6 doi: 10.1101/cshperspect.a026070. PubMed DOI PMC

Liu A., Takakuwa T., Fujita S., Ham M.F., Luo W.J., Daibata M., Aozasa K. Alterations of DNA damage-response genes ATM and ATR in pyothorax-associated lymphoma. Lab. Investig. J. Tech. Methods Pathol. 2005;85:436–446. doi: 10.1038/labinvest.3700235. PubMed DOI

Schaffner C., Idler I., Stilgenbauer S., Dohner H., Lichter P. Mantle cell lymphoma is characterized by inactivation of the ATM gene. Proc. Natl. Acad. Sci. USA. 2000;97:2773–2778. doi: 10.1073/pnas.050400997. PubMed DOI PMC

Rossi D., Rasi S., Spina V., Bruscaggin A., Monti S., Ciardullo C., Deambrogi C., Khiabanian H., Serra R., Bertoni F., et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013;121:1403–1412. doi: 10.1182/blood-2012-09-458265. PubMed DOI PMC

Gonzalez D., Martinez P., Wade R., Hockley S., Oscier D., Matutes E., Dearden C.E., Richards S.M., Catovsky D., Morgan G.J. Mutational status of the Tp53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: Results from the LRF CLL4 trial. J. Clin. Oncol. 2011;29:2223–2229. doi: 10.1200/JCO.2010.32.0838. PubMed DOI

Te Raa G.D., Malcikova J., Pospisilova S., Trbusek M., Mraz M., Garff-Tavernier M.L., Merle-Beral H., Lin K., Pettitt A.R., Merkel O., et al. Overview of available p53 function tests in relation to Tp53 and ATM gene alterations and chemoresistance in chronic lymphocytic leukemia. Leuk. Lymphoma. 2013;54:1849–1853. doi: 10.3109/10428194.2013.796058. PubMed DOI

Cesarman E., Inghirami G., Chadburn A., Knowles D.M. High levels of p53 protein expression do not correlate with p53 gene mutations in anaplastic large cell lymphoma. Am. J. Pathol. 1993;143:845–856. PubMed PMC

Rassidakis G.Z., Thomaides A., Wang S., Jiang Y., Fourtouna A., Lai R., Medeiros L.J. P53 gene mutations are uncommon but p53 is commonly expressed in anaplastic large-cell lymphoma. Leukemia. 2005;19:1663–1669. doi: 10.1038/sj.leu.2403840. PubMed DOI

Boi M., Rinaldi A., Kwee I., Bonetti P., Todaro M., Tabbo F., Piva R., Rancoita P.M., Matolcsy A., Timar B., et al. PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood. 2013;122:2683–2693. doi: 10.1182/blood-2013-04-497933. PubMed DOI

Leventaki V., Drakos E., Medeiros L.J., Lim M.S., Elenitoba-Johnson K.S., Claret F.X., Rassidakis G.Z. NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/CJUN signaling in anaplastic large-cell lymphoma. Blood. 2007;110:1621–1630. doi: 10.1182/blood-2006-11-059451. PubMed DOI

Cui Y.X., Kerby A., McDuff F.K., Ye H., Turner S.D. NPM-ALK inhibits the p53 tumor suppressor pathway in an MDM2 and JNK-dependent manner. Blood. 2009;113:5217–5227. doi: 10.1182/blood-2008-06-160168. PubMed DOI

McDuff F.K., Turner S.D. Aberrant anaplastic lymphoma kinase activity induces a p53 and RB-dependent senescence-like arrest in the absence of detectable p53 stabilization. PLoS ONE. 2011;6:e17854. doi: 10.1371/journal.pone.0017854. PubMed DOI PMC

Chen Z., Trotman L.C., Shaffer D., Lin H.K., Dotan Z.A., Niki M., Koutcher J.A., Scher H.I., Ludwig T., Gerald W., et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436:725–730. doi: 10.1038/nature03918. PubMed DOI PMC

Ventura A., Kirsch D.G., McLaughlin M.E., Tuveson D.A., Grimm J., Lintault L., Newman J., Reczek E.E., Weissleder R., Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445:661–665. doi: 10.1038/nature05541. PubMed DOI

Vassilev L.T., Vu B.T., Graves B., Carvajal D., Podlaski F., Filipovic Z., Kong N., Kammlott U., Lukacs C., Klein C., et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–848. doi: 10.1126/science.1092472. PubMed DOI

Drakos E., Atsaves V., Schlette E., Li J., Papanastasi I., Rassidakis G.Z., Medeiros L.J. The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53. Leukemia. 2009;23:2290–2299. doi: 10.1038/leu.2009.180. PubMed DOI

Collado M., Blasco M.A., Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130:223–233. doi: 10.1016/j.cell.2007.07.003. PubMed DOI

Collado M., Serrano M. The power and the promise of oncogene-induced senescence markers. Nat. Rev. Cancer. 2006;6:472–476. doi: 10.1038/nrc1884. PubMed DOI

Shapiro G.I., Edwards C.D., Kobzik L., Godleski J., Richards W., Sugarbaker D.J., Rollins B.J. Reciprocal RB inactivation and p16ink4 expression in primary lung cancers and cell lines. Cancer Res. 1995;55:505–509. PubMed

Martinelli P., Bonetti P., Sironi C., Pruneri G., Fumagalli C., Raviele P.R., Volorio S., Pileri S., Chiarle R., McDuff F.K., et al. The lymphoma-associated NPM-ALK oncogene elicits a P16INK4A/PRB-dependent tumor-suppressive pathway. Blood. 2011;117:6617–6626. doi: 10.1182/blood-2010-08-301135. PubMed DOI

Trotta R., Vignudelli T., Candini O., Intine R.V., Pecorari L., Guerzoni C., Santilli G., Byrom M.W., Goldoni S., Ford L.P., et al. BCR/ABL activates MDM2 mrna translation via the la antigen. Cancer Cell. 2003;3:145–160. doi: 10.1016/S1535-6108(03)00020-5. PubMed DOI

Insinga A., Monestiroli S., Ronzoni S., Carbone R., Pearson M., Pruneri G., Viale G., Appella E., Pelicci P., Minucci S. Impairment of p53 acetylation, stability and function by an oncogenic transcription factor. EMBO J. 2004;23:1144–1154. doi: 10.1038/sj.emboj.7600109. PubMed DOI PMC

Ceccon M., Merlo M.E.B., Mologni L., Poggio T., Varesio L.M., Menotti M., Bombelli S., Rigolio R., Manazza A.D., Di Giacomo F., et al. Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency. Oncogene. 2016;35:3854–3865. doi: 10.1038/onc.2015.456. PubMed DOI PMC

Ceccon M., Mologni L., Giudici G., Piazza R., Pirola A., Fontana D., Gambacorti-Passerini C. Treatment efficacy and resistance mechanisms using the second-generation ALK inhibitor ap26113 in human NPM-ALK-positive anaplastic large cell lymphoma. Mol. Cancer Res. 2015;13:775–783. doi: 10.1158/1541-7786.MCR-14-0157. PubMed DOI

Zdzalik D., Dymek B., Grygielewicz P., Gunerka P., Bujak A., Lamparska-Przybysz M., Wieczorek M., Dzwonek K. Activating mutations in ALK kinase domain confer resistance to structurally unrelated ALK inhibitors in NPM-ALK-positive anaplastic large-cell lymphoma. J. Cancer Res. Clin. Oncol. 2014;140:589–598. doi: 10.1007/s00432-014-1589-3. PubMed DOI PMC

Altieri F., Grillo C., Maceroni M., Chichiarelli S. DNA damage and repair: From molecular mechanisms to health implications. Antioxid. Redox Signaling. 2008;10:891–937. doi: 10.1089/ars.2007.1830. PubMed DOI

Lindahl T., Barnes D.E. Repair of endogenous DNA damage. Cold Spring Harb. Symp. Quant. Biol. 2000;65:127–133. doi: 10.1101/sqb.2000.65.127. PubMed DOI

Taylor E.M., Lehmann A.R. Conservation of eukaryotic DNA repair mechanisms. Intern. J. Radiat. Biol. 1998;74:277–286. PubMed

Modrich P., Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Ann. Rev. Biochem. 1996;65:101–133. doi: 10.1146/annurev.bi.65.070196.000533. PubMed DOI

Kunkel T.A., Erie D.A. DNA mismatch repair. Ann. Rev. Biochem. 2005;74:681–710. doi: 10.1146/annurev.biochem.74.082803.133243. PubMed DOI

Acharya S., Wilson T., Gradia S., Kane M.F., Guerrette S., Marsischky G.T., Kolodner R., Fishel R. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc. Natl. Acad. Sci. USA. 1996;93:13629–13634. doi: 10.1073/pnas.93.24.13629. PubMed DOI PMC

Li G.M. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008;18:85–98. doi: 10.1038/cr.2007.115. PubMed DOI

Modrich P. Mechanisms in eukaryotic mismatch repair. J. Biol. Chem. 2006;281:30305–30309. doi: 10.1074/jbc.R600022200. PubMed DOI PMC

Prolla T.A., Christie D.M., Liskay R.M. Dual requirement in yeast DNA mismatch repair for MLH1 and PMS1, two homologs of the bacterial mutL gene. Mol. Cell. Biol. 1994;14:407–415. doi: 10.1128/MCB.14.1.407. PubMed DOI PMC

Guo S., Presnell S.R., Yuan F., Zhang Y., Gu L., Li G.M. Differential requirement for proliferating cell nuclear antigen in 5’ and 3’ nick-directed excision in human mismatch repair. J. Biol. Chem. 2004;279:16912–16917. doi: 10.1074/jbc.M313213200. PubMed DOI

Nielsen F.C., Jager A.C., Lutzen A., Bundgaard J.R., Rasmussen L.J. Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with pcna. Oncogene. 2004;23:1457–1468. doi: 10.1038/sj.onc.1207265. PubMed DOI

Tran P.T., Erdeniz N., Symington L.S., Liskay R.M. EXO1-a multi-tasking eukaryotic nuclease. DNA Repair. 2004;3:1549–1559. doi: 10.1016/j.dnarep.2004.05.015. PubMed DOI

Liu D., Keijzers G., Rasmussen L.J. DNA mismatch repair and its many roles in eukaryotic cells. Mutat. Res. 2017;773:174–187. doi: 10.1016/j.mrrev.2017.07.001. PubMed DOI

Tiraby J.G., Fox M.S. Marker discrimination in transformation and mutation of pneumococcus. Proc. Natl. Acad. Sci. USA. 1973;70:3541–3545. doi: 10.1073/pnas.70.12.3541. PubMed DOI PMC

Lynch H.T., de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J. Med. Genet. 1999;36:801–818. PubMed PMC

Hampel H., Frankel W.L., Martin E., Arnold M., Khanduja K., Kuebler P., Nakagawa H., Sotamaa K., Prior T.W., Westman J., et al. Screening for the lynch syndrome (hereditary nonpolyposis colorectal cancer) N. Engl. J. Med. 2005;352:1851–1860. doi: 10.1056/NEJMoa043146. PubMed DOI

Barnetson R.A., Tenesa A., Farrington S.M., Nicholl I.D., Cetnarskyj R., Porteous M.E., Campbell H., Dunlop M.G. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N. Engl. J. Med. 2006;354:2751–2763. doi: 10.1056/NEJMoa053493. PubMed DOI

Fink D., Nebel S., Norris P.S., Aebi S., Kim H.K., Haas M., Howell S.B. The effect of different chemotherapeutic agents on the enrichment of DNA mismatch repair-deficient tumour cells. Br. J. Cancer. 1998;77:703–708. doi: 10.1038/bjc.1998.116. PubMed DOI PMC

Edelmann W., Yang K., Umar A., Heyer J., Lau K., Fan K., Liedtke W., Cohen P.E., Kane M.F., Lipford J.R., et al. Mutation in the mismatch repair gene msh6 causes cancer susceptibility. Cell. 1997;91:467–477. doi: 10.1016/S0092-8674(00)80433-X. PubMed DOI

Reitmair A.H., Schmits R., Ewel A., Bapat B., Redston M., Mitri A., Waterhouse P., Mittrucker H.W., Wakeham A., Liu B., et al. MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nat. Genet. 1995;11:64–70. doi: 10.1038/ng0995-64. PubMed DOI

Baker S.M., Plug A.W., Prolla T.A., Bronner C.E., Harris A.C., Yao X., Christie D.M., Monell C., Arnheim N., Bradley A., et al. Involvement of mouse MLH1 in DNA mismatch repair and meiotic crossing over. Nat. Genet. 1996;13:336–342. doi: 10.1038/ng0796-336. PubMed DOI

Prolla T.A., Baker S.M., Harris A.C., Tsao J.L., Yao X., Bronner C.E., Zheng B., Gordon M., Reneker J., Arnheim N., et al. Tumour susceptibility and spontaneous mutation in mice deficient in MLH1, PMS1 and PMS2 DNA mismatch repair. Nat. Genet. 1998;18:276–279. doi: 10.1038/ng0398-276. PubMed DOI

Wei K., Clark A.B., Wong E., Kane M.F., Mazur D.J., Parris T., Kolas N.K., Russell R., Hou H., Jr., Kneitz B., et al. Inactivation of exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. Genes Dev. 2003;17:603–614. doi: 10.1101/gad.1060603. PubMed DOI PMC

Wu F., Wang P., Young L.C., Lai R., Li L. Proteome-wide identification of novel binding partners to the oncogenic fusion gene protein, NPM-ALK, using tandem affinity purification and mass spectrometry. Am. J. Pathol. 2009;174:361–370. doi: 10.2353/ajpath.2009.080521. PubMed DOI PMC

Young L.C., Bone K.M., Wang P., Wu F., Adam B.A., Hegazy S., Gelebart P., Holovati J., Li L., Andrew S.E., et al. Fusion tyrosine kinase NPM-ALK deregulates MSH2 and suppresses DNA mismatch repair function novel insights into a potent oncoprotein. Am. J. Pathol. 2011;179:411–421. doi: 10.1016/j.ajpath.2011.03.045. PubMed DOI PMC

Bone K.M., Wang P., Wu F., Wu C., Li L., Bacani J.T., Andrew S.E., Lai R. Npm-alk mediates phosphorylation of msh2 at tyrosine 238, creating a functional deficiency in MSH2 and the loss of mismatch repair. Blood Cancer J. 2015;5:e311. doi: 10.1038/bcj.2015.35. PubMed DOI PMC

Wu J., Savooji J., Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J. Hematol. Oncol. 2016;9:19. doi: 10.1186/s13045-016-0251-8. PubMed DOI PMC

Andreeff M., Kelly K.R., Yee K., Assouline S., Strair R., Popplewell L., Bowen D., Martinelli G., Drummond M.W., Vyas P., et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin. Cancer Res. 2016;22:868–876. doi: 10.1158/1078-0432.CCR-15-0481. PubMed DOI PMC

Ding Q., Zhang Z., Liu J.J., Jiang N., Zhang J., Ross T.M., Chu X.J., Bartkovitz D., Podlaski F., Janson C., et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J. Med. Chem. 2013;56:5979–5983. doi: 10.1021/jm400487c. PubMed DOI

Herting F., Herter S., Friess T., Muth G., Bacac M., Sulcova J., Umana P., Dangl M., Klein C. Antitumour activity of the glycoengineered type II anti-CD20 antibody obinutuzumab (GA101) in combination with the MDM2-selective antagonist idasanutlin (RG7388) Eur. J. Haematol. 2016;97:461–470. doi: 10.1111/ejh.12756. PubMed DOI