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The role of p53 in myelodysplastic syndromes and acute myeloid leukemia: molecular aspects and clinical implications

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Pages 1777-1790 | Received 12 Oct 2016, Accepted 22 Nov 2016, Published online: 14 Dec 2016

References

  • Isobe M, Emanuel BS, Givol D, et al. Localization of gene for human p53 tumour antigen to band 17p13. Nature. 1986;320:84–85.
  • Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–331.
  • Havre PA, Yuan J, Hedrick L, et al. p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. Cancer Res. 1995;55:4420–4424.
  • Bouffler SD, Kemp CJ, Balmain A, et al. Spontaneous and ionizing radiation-induced chromosomal abnormalities in p53-deficient mice. Cancer Res. 1995;55:3883–3889.
  • Livingstone LR, White A, Sprouse J, et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992;70:923–935.
  • Gualberto A, Aldape K, Kozakiewicz K, et al. An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci USA.1998;95:5166–5171.
  • O'Connor PM, Fan S. DNA damage checkpoints: implications for cancer therapy. Prog Cell Cycle Res. 1996;2:165–173.
  • Ferreira CG, Tolis C, Giaccone G. p53 and chemosensitivity. Ann Oncol. 1999;10:1011–1021.
  • Carson DA, Lois A. Cancer progression and p53. Lancet. 1995;346:1009–1011.
  • Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004;4:793–805.
  • Xu-Monette ZY, Medeiros LJ, Li Y, et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood. 2012;119:3668–3683.
  • Vousden KH, Lu X. Live or let die: the cell's response to p53. Nat Rev Cancer. 2002;2:594–604.
  • Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310.
  • Olivier M, Hussain SP, Caron de Fromentel C, et al. TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ. 2004;157:247–270.
  • Aschauer L, Muller PA. Novel targets and interaction partners of mutant p53 Gain-Of-Function. Biochem Soc Trans. 2016;44:460–466.
  • Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005;24:2899–2908.
  • MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.
  • Fuchs O. Important genes in the pathogenesis of 5q- syndrome and their connection with ribosomal stress and the innate immune system pathway. Leuk Res Treatment. 2012;2012:179402.
  • Hunten S, Siemens H, Kaller M, et al. The p53/microRNA network in cancer: experimental and bioinformatics approaches. Adv Exp Med Biol. 2013;774:77–101.
  • Marine JC, Lozano G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 2010;17:93–102.
  • Roth J, Dobbelstein M, Freedman DA, et al. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. Embo J. 1998;17:554–564.
  • Wang X, Jiang X. Mdm2 and MdmX partner to regulate p53. FEBS Lett. 2012;586:1390–1396.
  • Mendoza M, Mandani G, Momand J. The MDM2 gene family. Biomol Concepts. 2014;5:9–19.
  • Juven T, Barak Y, Zauberman A, et al. Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene. Oncogene. 1993;8:3411–3416.
  • Wu X, Bayle JH, Olson D, et al. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7:1126–1132.
  • Zhou X, Liao JM, Liao WJ, et al. Scission of the p53-MDM2 loop by ribosomal proteins. Genes Cancer. 2012;3:298–310.
  • Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–1376.
  • Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496–2506.
  • Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25:1147–1152.
  • Malcovati L, Cazzola M. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts. Br J Haematol. 2016;174:847–858.
  • Cazzola M, Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood. 2013;122:4021–4034.
  • Zhang L, Padron E, Lancet J. The molecular basis and clinical significance of genetic mutations identified in myelodysplastic syndromes. Leuk Res. 2015;39:6–17.
  • Kulasekararaj AG, Smith AE, Mian SA, et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol. 2013;160:660–672.
  • Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol. 2001;19:1405–1413.
  • Kaneko H, Misawa S, Horiike S, et al. TP53 mutations emerge at early phase of myelodysplastic syndrome and are associated with complex chromosomal abnormalities. Blood. 1995;85:2189–2193.
  • Cleven AH, Nardi V, Ok CY, et al. High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome. Mod Pathol. 2015;28:552–563.
  • Kita-Sasai Y, Horiike S, Misawa S, et al. International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. Br J Haematol. 2001;115:309–312.
  • Jadersten M, Saft L, Smith A, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011;29:1971–1979.
  • Kwok B, Hall JM, Witte JS, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood. 2015;126:2355–2361.
  • Sallman DA, Komrokji R, Vaupel C, et al. Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes. Leukemia. 2016;30:666–673.
  • Belickova M, Vesela J, Jonasova A, et al. TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes. Oncotarget. 2016;7:36266–36279.
  • Fenaux P, Giagounidis A, Selleslag D, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118:3765–3776.
  • Saft L, Karimi M, Ghaderi M, et al. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Haematologica. 2014;99:1041–1049.
  • Loghavi S, Al-Ibraheemi A, Zuo Z, et al. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis. Br J Haematol. 2015;171:91–99.
  • Ramos F, Robledo C, Izquierdo-Garcia FM, et al. Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis. Oncotarget. 2016;7:30492–30503.
  • Nishiwaki S, Ito M, Watarai R, et al. A new prognostic index to make short-term prognoses in MDS patients treated with azacitidine: a combination of p53 expression and cytogenetics. Leuk Res. 2016;41:21–26.
  • McGraw KL, Nguyen J, Komrokji RS, et al. Immunohistochemical pattern of p53 is a measure of TP53 mutation burden and adverse clinical outcome in myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica. 2016;10:e320–323.
  • Bektas O, Uner A, Buyukasik Y, et al. Clinical and pathological correlations of marrow PUMA and P53 expressions in myelodysplastic syndromes. Apmis. 2015;123:445–451.
  • Hofmann WK, Lubbert M, Hoelzer D, et al. Myelodysplastic syndromes. Hematol J. 2004;5:1–8.
  • Giagounidis AA, Germing U, Aul C. Biological and prognostic significance of chromosome 5q deletions in myeloid malignancies. Clin Cancer Res. 2006;12:5–10.
  • Haase D, Germing U, Schanz J, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007;110:4385–4395.
  • Sole F, Espinet B, Sanz GF, et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Espanol de Citogenetica Hematologica. Br J Haematol. 2000;108:346–356.
  • Vardiman J. The classification of MDS: from FAB to WHO and beyond. Leuk Res. 2012;36:1453–1458.
  • Vardiman JW. The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues: an overview with emphasis on the myeloid neoplasms. Chem Biol Interact. 2010;184:16–20.
  • Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–951.
  • Ebert BL. Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer. Leukemia. 2009;23:1252–1256.
  • Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q-syndrome gene by RNA interference screen. Nature. 2008;451:335–339.
  • Komrokji RS, Padron E, Ebert BL, et al. Deletion 5q MDS: molecular and therapeutic implications. Best Pract Res Clin Haematol. 2013;26:365–375.
  • Abou Zahr A, Saad Aldin E, Komrokji RS, et al. Clinical utility of lenalidomide in the treatment of myelodysplastic syndromes. J Blood Med. 2015;6:1–16.
  • Wei S, Chen X, Rocha K, et al. A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci USA. 2009;106:12974–12979.
  • Ebert BL. Molecular dissection of the 5q deletion in myelodysplastic syndrome. Semin Oncol. 2011;38:621–626.
  • Barlow JL, Drynan LF, Hewett DR, et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nat Med. 2010;16:59–66.
  • Schneider RK, Schenone M, Ferreira MV, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016;22:288–297.
  • Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 2009;49:223–241.
  • Lau LM, Nugent JK, Zhao X, et al. HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene. 2008;27:997–1003.
  • Dutt S, Narla A, Lin K, et al. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood. 2011;117:2567–2576.
  • Sherr CJ. Divorcing ARF and p53: an unsettled case. Nat Rev Cancer. 2006;6:663–673.
  • Hay TJ, Meek DW. Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains. FEBS Lett. 2000;478:183–186.
  • Maya R, Balass M, Kim ST, et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev. 2001;15:1067–1077.
  • Brooks CL, Gu W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol. 2003;15:164–171.
  • Melchior F, Hengst L. SUMO-1 and p53. Cell Cycle. 2002;1:245–249.
  • Sulic S, Panic L, Barkic M, et al. Inactivation of S6 ribosomal protein gene in T lymphocytes activates a p53-dependent checkpoint response. Genes Dev. 2005;19:3070–3082.
  • Zhang Y, Wolf GW, Bhat K, et al. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol. 2003;23:8902–8912.
  • Dai MS, Lu H. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J Biol Chem. 2004;279:44475–44482.
  • Jin A, Itahana K, O'Keefe K, et al. Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol. 2004;24:7669–7680.
  • Alkhatabi HA, McLornan DP, Kulasekararaj AG, et al. RPL27A is a target of miR-595 and may contribute to the myelodysplastic phenotype through ribosomal dysgenesis. Oncotarget. 2016;7:47875–47890.
  • He H, Sun Y. Ribosomal protein S27L is a direct p53 target that regulates apoptosis. Oncogene. 2007;26:2707–2716.
  • Li J, Tan J, Zhuang L, et al. Ribosomal protein S27-like, a p53-inducible modulator of cell fate in response to genotoxic stress. Cancer Res. 2007;67:11317–11326.
  • Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233.
  • Boultwood J, Pellagatti A, Cattan H, et al. Gene expression profiling of CD34+ cells in patients with the 5q- syndrome. Br J Haematol. 2007;139:578–589.
  • Starczynowski DT, Kuchenbauer F, Argiropoulos B, et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010;16:49–58.
  • Narla A, Hurst SN, Ebert BL. Ribosome defects in disorders of erythropoiesis. Int J Hematol. 2011;93:144–149.
  • Kumar MS, Narla A, Nonami A, et al. Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q-syndrome. Blood. 2011;118:4666–4673.
  • Pellagatti A, Boultwood J. Recent advances in the 5q-syndrome. Mediterr J Hematol Infect Dis. 2015;7:e2015037.
  • Chen X, Eksioglu EA, Zhou J, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123:4595–4611.
  • Wei Y, Chen R, Dimicoli S, et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia. 2013;27:2177–2186.
  • List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–1465.
  • Komrokji RS, List AF. Short- and long-term benefits of lenalidomide treatment in patients with lower-risk del(5q) myelodysplastic syndromes. Ann Oncol. 2016;27:62–68.
  • Giagounidis A, Mufti GJ, Fenaux P, et al. Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes. Ann Hematol. 2014;93:1–11.
  • Wei S, Chen X, McGraw K, et al. Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. Oncogene. 2013;32:1110–1120.
  • Sallman DA, Wei S, List A. PP2A: the achilles heal in MDS with 5q deletion. Front Oncol. 2014;4:264
  • McGraw KL, Cluzeau T, Sallman DA, et al. TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes. Oncotarget. 2015;6:34437–34445.
  • McGraw KL, Zhang LM, Rollison DE, et al. The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes. Blood Cancer J. 2015;5:e291.
  • Lai JL, Preudhomme C, Zandecki M, et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia. 1995;9:370–381.
  • Soenen V, Preudhomme C, Roumier C, et al. 17p deletion in acute myeloid leukemia and myelodysplastic syndrome. Analysis of breakpoints and deleted segments by fluorescence in situ. Blood. 1998;91:1008–1015.
  • Komrokji RS, Lancet JE, Swern AS, et al. Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood. 2012;120:3419–3424.
  • Chesnais V, Renneville A, Toma A, et al. Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion. Blood. 2016;127:749–760.
  • Fang J, Liu X, Bolanos L, et al. A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. Nat Med. 2016;22:727–734.
  • Moutouh-de Parseval LA, Verhelle D, Glezer E, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest. 2008;118:248–258.
  • McGraw KL, Fuhler GM, Johnson JO, et al. Erythropoietin receptor signaling is membrane raft dependent. PLoS One. 2012;7:e34477.
  • Basiorka AA, McGraw KL, De Ceuninck L, et al. Lenalidomide stabilizes the erythropoietin receptor by inhibiting the E3 ubiquitin ligase RNF41. Cancer Res. 2016;76:3531–3540.
  • Murati A, Brecqueville M, Devillier R, et al. Myeloid malignancies: mutations, models and management. BMC Cancer. 2012;12:304.
  • Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–2074.
  • Fenaux P, Preudhomme C, Quiquandon I, et al. Mutations of the P53 gene in acute myeloid leukaemia. Br J Haematol. 1992;80:178–183.
  • Slingerland JM, Minden MD, Benchimol S. Mutation of the p53 gene in human acute myelogenous leukemia. Blood. 1991;77:1500–1507.
  • Fenaux P, Jonveaux P, Quiquandon I, et al. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood. 1991;78:1652–1657.
  • Hou HA, Chou WC, Kuo YY, et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Blood Cancer J. 2015;5:e331.
  • Ok CY, Patel KP, Garcia-Manero G, et al. TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. J Hematol Oncol. 2015;8:45.
  • Haferlach C, Dicker F, Herholz H, et al. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia. 2008;22:1539–1541.
  • Bowen D, Groves MJ, Burnett AK, et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia. 2009;23:203–206.
  • Grossmann V, Schnittger S, Kohlmann A, et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood. 2012;120:2963–2972.
  • Renneville A, Roumier C, Biggio V, et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008;22:915–931.
  • Devillier R, Mansat-De Mas V, Gelsi-Boyer V, et al. Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes. Oncotarget. 2015;6:8388–8396.
  • Breems DA, Van Putten WL, De Greef GE, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26:4791–4797.
  • Rucker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119:2114–2121.
  • Middeke JM, Beelen D, Stadler M, et al. Outcome of high-risk acute myeloid leukemia after allogeneic hematopoietic cell transplantation: negative impact of abnl(17p) and -5/5q-. Blood. 2012;120:2521–2528.
  • Liu Y, Chen C, Xu Z, et al. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature. 2016;531:471–475.
  • Fang M, Storer B, Estey E, et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Blood. 2011;118:1490–1494.
  • Middeke JM, Fang M, Cornelissen JJ, et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood. 2014;123:2960–2967.
  • Orazi A, Cattoretti G, Heerema NA, et al. Frequent p53 overexpression in therapy related myelodysplastic syndromes and acute myeloid leukemias: an immunohistochemical study of bone marrow biopsies. Mod Pathol. 1993;6:521–525.
  • Sahu G, Jena RK. Clinical significance of P53 and Bcl-2 in acute myeloid leukemia patients of Eastern India. Hematol Rep. 2011;3:e28.
  • Mattsson K, Honkaniemi E, Barbany G, et al. Increased p53 protein expression as a potential predictor of early relapse after hematopoietic stem cell transplantation in children with acute myelogenous leukemia. Pediatr Transplant. 2015;19:767–775.
  • Zhao Z, Zuber J, Diaz-Flores E, et al. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev. 2010;24:1389–1402.
  • Zhang J, Kong G, Rajagopalan A, et al. p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia. Blood. 2016. [Epub ahead of print]. doi: 10.1182/blood-2016-06-719237.
  • Jaako P, Flygare J, Olsson K, et al. Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia. Blood. 2011;118:6087–6096.
  • Jaako P, Debnath S, Olsson K, et al. Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia. Leukemia. 2015;29:2221–2229.
  • Jaako P, Ugale A, Wahlestedt M, et al. Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia. Leukemia. 2016. [Epub ahead of print]. doi: 10.1038/leu.2016.159.
  • Deisenroth C, Zhang Y. The ribosomal protein-Mdm2-p53 pathway and energy metabolism: bridging the gap between feast and famine. Genes Cancer. 2011;2:392–403.
  • Macias E, Jin A, Deisenroth C, et al. An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction. Cancer Cell. 2010;18:231–243.
  • Han X, Medeiros LJ, Zhang YH, et al. High expression of human homologue of murine double minute 4 and the short splicing variant, HDM4-S, in bone marrow in patients with acute myeloid leukemia or myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk. 2016;16 Suppl:S30–S38.
  • Seipel K, Marques MT, Bozzini MA, et al. Inactivation of the p53-KLF4-CEBPA axis in acute myeloid leukemia. Clin Cancer Res. 2016;22:746–756.
  • Ferraiuolo M, Di Agostino S, Blandino G, et al. Oncogenic intra-p53 family member interactions in human cancers. Front Oncol. 2016;6:77
  • Liu YY. Resuscitating wild-type p53 expression by disrupting ceramide glycosylation: a novel approach to target mutant p53 tumors. Cancer Res. 2011;71:6295–6299.
  • Yuan Y, Liao YM, Hsueh CT, et al. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol. 2011;4:16.
  • Lehmann C, Friess T, Birzele F, et al. Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models. J Hematol Oncol. 2016;9:50.
  • Petzold G, Fischer ES, Thoma NH. Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase. Nature. 2016;532:127–130.
  • Hong CS, Ho W, Zhang C, et al. LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential. Cancer Biol Ther. 2015;16:821–833.
  • Drygin D, O'Brien SE, Hannan RD, et al. Targeting the nucleolus for cancer-specific activation of p53. Drug Discov Today. 2014;19:259–265.
  • Bywater MJ, Poortinga G, Sanij E, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 2012;22:51–65.
  • Alachkar H, Xie Z, Marcucci G, et al. Determination of cellular uptake and intracellular levels of Cenersen (Aezea((R)), EL625), a p53 antisense oligonucleotide in acute myeloid leukemia cells. J Pharm Biomed Anal. 2012;71:228–232.
  • Caceres G, McGraw K, Yip BH, et al. TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients. Proc Natl Acad Sci USA. 2013;110:16127–16132.
  • Urban G, Golden T, Aragon IV, et al. Identification of a functional link for the p53 tumor suppressor protein in dexamethasone-induced growth suppression. J Biol Chem. 2003;278:9747–9753.
  • Bayever E, Haines KM, Iversen PL, et al. Selective cytotoxicity to human leukemic myeloblasts produced by oligodeoxyribonucleotide phosphorothioates complementary to p53 nucleotide sequences. Leuk Lymphoma. 1994;12:223–231.
  • Papaphilis AD, Kamper EF, Grammenou S, et al. RNase H of human leukemic cells: a new biological parameter in the study of human leukemias (review). Anticancer Res. 1990;10:1201–1212.
  • Schittek B, Sinnberg T. Biological functions of casein kinase 1 isoforms and putative roles in tumorigenesis. Mol Cancer. 2014;13:231.
  • Knippschild U, Gocht A, Wolff S, et al. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal. 2005;17:675–689.
  • Price MA. CKI, there's more than one: casein kinase I family members in Wnt and Hedgehog signaling. Genes Dev. 2006;20:399–410.
  • Cheong JK, Virshup DM. Casein kinase 1: complexity in the family. Int J Biochem Cell Biol. 2011;43:465–469.
  • Chen L, Li C, Pan Y, et al. Regulation of p53-MDMX interaction by casein kinase 1 alpha. Mol Cell Biol. 2005;25:6509–6520.
  • Huart AS, MacLaine NJ, Meek DW, et al. CK1alpha plays a central role in mediating MDM2 control of p53 and E2F-1 protein stability. J Biol Chem. 2009;284:32384–32394.
  • Zelenak C, Eberhard M, Jilani K, et al. Protein kinase CK1α regulates erythrocyte survival. Cell Physiol Biochem. 2012;29:171–180.
  • Jaras M, Miller PG, Chu LP, et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J Exp Med. 2014;211:605–612.
  • Tabe Y, Sebasigari D, Jin L, et al. MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin Cancer Res. 2009;15:933–942.
  • Chene P. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer. 2003;3:102–109.
  • Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016;22:868–876.
  • Weisberg E, Halilovic E, Cooke VG, et al. Inhibition of wild-type p53-expressing AML by the novel small molecule HDM2 inhibitor CGM097. Mol Cancer Ther. 2015;14:2249–2259.
  • Di Agostino S, Cortese G, Monti O, et al. The disruption of the protein complex mutantp53/p73 increases selectively the response of tumor cells to anticancer drugs. Cell Cycle. 2008;7:3440–3447.
  • Guida E, Bisso A, Fenollar-Ferrer C, et al. Peptide aptamers targeting mutant p53 induce apoptosis in tumor cells. Cancer Res. 2008;68:6550–6558.
  • Zhang S, Zhou L, Hong B, et al. Small-molecule NSC59984 restores p53 pathway signaling and antitumor effects against colorectal cancer via p73 activation and degradation of mutant p53. Cancer Res. 2015;75:3842–3852.
  • Leitch C, Osdal T, Andresen V, et al. Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia. Oncotarget. 2016;7:8105–8118.
  • Ruvolo PP, Ruvolo VR, Benton CB, et al. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells. Biochim Biophys Acta. 2016;1863:562–571.

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