In order to ascertain whether p53 has a role in chronic myeloid leukemia hematopoietic progenitor response to the innovative tyrosine kinase inhibitor STI571 (Imatinib), we overexpressed a wild type (wt) p53 construct in the K562 cell line, generated from a human blast crisis and lacking endogenous p53. Wt p53 overexpression was associated with a significant reduction of bcr-abl expression levels resulting, at least in part, from post-transcriptional events affecting the stability of p210 bcr-abl fusion protein. Moreover, we demonstrated that p53 overexpression enhances the commitment to the apoptotic death fate of K562 following its in vitro exposure to 1 µM STI571. Multiple mechanisms are involved in p53 impact on K562 survival: Most importantly, we found that a greater reduction of bcr-abl transcription by STI571 was associated with the overexpression of wt p53. Further studies are required to elucidate the mechanisms involved in the transcriptional repression of bcr-abl by STI571 and p53 and in their synergic effects on the clonal hematopoiesis of chronic myeloid leukemia.

El-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y: WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994;54:1169–1174.
Wu Y, Mehew JW, Heckman CA, Arcinas M, Boxer LM: Negative regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene 2001;20:240–251.
Miller C: Human p53 gene localized to short arm of chromosome 17. Nature 1986;319:783–784.
Brusa G, Benvenuti M, Mazzacurati L, Mancini M, Pattacini L, Martinelli G, Barbieri E, Greenberger JS, Baccarani M, Santucci MA: P53 loss of function enhances genomic instability and accelerates clonal evolution of murine myeloid progenitors expressing the p210BCR-ABL tyrosine kinase. Haematologica 2003;88:622–630.
Honda H, Ushijima T, Wakazono K, Oda H, Tanaka Y, Aizawa S, Ishikawa T, Yazaki Y, Hiray H: Acquired loss of p53 induces blastic transformation in p210bcr/abl-expressing hematopoietic cells: a transgenic study for blast crisis of human CML. Blood 2000;95:1144–1150.
Lozzio CB, Lozzio BB: Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 1975;45:321–334.
Law JC, Ritke MK, Yalowich JC, Leder GH, Ferrell RE: Mutational inactivation of the p53 gene in the human erythroid leukemic K562 cell line. Leuk Res 1993;17:1045–1050.
Soddu S, Sacchi A: p53: prospects for cancer gene therapy. Cytokines Cell Mol Ther 1998;4:177–185.
Yamashita K, Yasuda H, Pines J, Yasumoto K, Nishitani H, Ohtsubo M, Hunter T, Sugimura T, Nishimoto T: Okadaic acid, a potent inhibitor of type 1 and type 2A protein phosphatases, activates cdc2/H1 kinase and transiently induces a premature mitosis-like state in BHK21 cells. EMBO J 1990;9:4331–4338.
Campanini F, Santucci MA, Pattacini L, Brusa G, Piccioli M, Barbieri E, Babibi L, Tura S: Competitive polymerase chain reaction as a method to detect the amplification of bcr-abl gene of chronic myeloid leukemia. Haematologica 2001;86:167–173.
Diviacco S, Norio P, Zentilin L, Menzo S, Clementi M, Biamonti G, RivaS, Falaschi A, Giacca M: A novel procedure for quantitative polymerase chain reaction by coamplification of competitive templates. Gene 1992;122:313–320.
Campanini F, Santucci MA, Brusa G, Pattacini L, Arpinati M, Rondelli D, Gamberi B, Barbieri E, Babini L, Tura S: Expression of P21(WAF1/CIP1/SID1) cyclin-dependent kinase inhibitor in hematopoietic progenitor cells. Gene 2001;273:173–180.
Di Bacco AM, Cotter TG: P53 expression in K562 cells is associated with caspase-mediated cleavage of c-ABL and BCR-ABL protein kinases. Br J Haematol 2002;117:588–597.
Corbin AS, Buchdunger E, Pascal F, Druker BJ: Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem 2002;277:32214–32219.
Pattacini L, Mancini M, Mazzacurati L, Brusa G, Benvenuti M, Martinelli G, Baccarani M, Santucci MA: Endoplasmic reticulum stress initiates apoptotic death induced by STI571 inhibition of p210bcr-abl tyrosine kinase. Leuk Res 2004;28:191–202.
Cummings M, Siitonen T, Higginbottom K, Newland AC, Allen PD: p53-mediated downregulation of Chk1 abrogates the DNA damage-induced G2M checkpoint in K562 cells, resulting in increased apoptosis. Br J Haematol 2002;116:421–428.
Trepel M, Scheding S, Groscurth P, Horny HP, Malipiero U, Brugger W, Dichgans J, Weller M: A new look at the role of p53 in leukemia cell sensitivity to chemotherapy. Leukemia 1997;11:1842–1849.
Mancini M, Brusa G, Benvenuti M, Mazzacurati L, Campanini F, Barbieri E, Cammelli S, Calonghi N, Martinelli G, Baccarani M, Santucci MA: The (p210)BCR-ABL tyrosine kinase of chronic myeloid leukemia causes resistance to radio-induced apoptotic death by inhibiting the proapoptotic BAX gene. Leukemia 2003;18:370–372.
Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C, Santilli G, Byrom MW, Goldono S, Ford LP, Caligiuri MA, Maraia RJ, Perrotti D, Calabretta B: BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell 2003;3:145–160.
Feng J, Tamaskovic R, Yang Z, Brazil DP, Merlo A, Hess D, Hemmings BA: Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. J Biol Chem 2004;279:35510–35517.
Kawauchi K, Ogasawara T, Yasuyama M, Ohkawa S: Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells. Blood Cells Mol Dis 2003;31:11–17.
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