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How can p53 induce differentiation of leukemic cells?

Drott, Kristina LU (2001)
Abstract (Swedish)
Popular Abstract in Swedish

p53 Ñett protein som kan fŒ leukemiceller att bli mera mogna



Vid akut leukemi ansamlas omogna blodceller med nedsatt fšrmŒga till utmognad och programmerad celldšd. Detta leder till frŒnvaro av normala blodceller, vilket Šr huvudorsaken till de infektioner och blšdningsrubbningar som utgšr leukemins frŠmsta symptom. Akut leukemi har hittills framfšr allt behandlats med hjŠlp av cellgifter vilket har lett till stora terapiframsteg och bot fšr mŒnga patienter. Men cellgifter kan ge upphov till svŒra biverkningar. Det kliniska intresset har dŠrfšr Šven riktats mot s k differentieringsterapi av akut leukemi. Differentieringsterapi syftar till att minska tumšrcellsmassan genom att... (More)
Popular Abstract in Swedish

p53 Ñett protein som kan fŒ leukemiceller att bli mera mogna



Vid akut leukemi ansamlas omogna blodceller med nedsatt fšrmŒga till utmognad och programmerad celldšd. Detta leder till frŒnvaro av normala blodceller, vilket Šr huvudorsaken till de infektioner och blšdningsrubbningar som utgšr leukemins frŠmsta symptom. Akut leukemi har hittills framfšr allt behandlats med hjŠlp av cellgifter vilket har lett till stora terapiframsteg och bot fšr mŒnga patienter. Men cellgifter kan ge upphov till svŒra biverkningar. Det kliniska intresset har dŠrfšr Šven riktats mot s k differentieringsterapi av akut leukemi. Differentieringsterapi syftar till att minska tumšrcellsmassan genom att tvinga de leukemiska cellerna till utmognad och den programmerade celldšd som oftast fšljer med fullstŠndig utmognad. Eftersom differentierings-terapi bšr kunna utformas sŒ att den framfšr allt pŒverkar leukemicellerna men inte skadar andra celler, skulle biverkningarna antagligen bli avsevŠrt mindre vid differentieringsterapi Šn vid cellgiftsbehandling.



VŒr forskning inriktar sig pŒ att finna vŠgar fšr att passera utmognadsblockaden vid akut leukemi fšr att nŒ fram till differentierings-terapi. Det hittills enda kliniskt framgŒngsrika exemplet Šr behandlingen av akut promyelocytleukemi, dŠr differentieringsterapi med vitamin A-syra i kombination med cytostatika numera Šr en vedertagen behandlingsmetod. PŒ laboratoriet kan emellertid ett flertal substanser (t ex vitamin D3, cytokiner) tvinga leukemiska celler att mogna ut. Dessa resultat har dock Šnnu ej gŒtt att applicera pŒ patienter. Ny kunskap kring blodcellers utmognad krŠvs dŠrfšr fšr att finna kliniskt verksamma sŠtt att fŒ leukemiceller att mogna ut och dŠrmed dš.



Det cancerskyddande proteinet p53 kan fšrhindra cancerutveckling genom att tvinga cancerceller till programmerad celldšd. Intressant nog kan p53, i alla fall i laboratoriet, Šven inducera utmognad hos leukemiska celler. Det ter sig dŠrfšr attraktivt att fšrsška anvŠnda sig av p53s sŠtt att inducera utmognad vid utformningen av alternativa behandlings-strategier fšr differentierings-terapi vid leukemi. MŒlet med min avhandling har dŠrfšr varit att bŠttre fšrstŒ vilka molekylŠra mekanismer som fšrmedlar p53inducerad utmognad. Vi har bl a visat att det inte behšvs lika mycket fungerande p53 fšr att fŒ leukemiceller att mogna ut, som det behšvs fšr att fŒ leukemiceller att begŒ programmerad celldšd. Detta skulle kunna innebŠra att Šven en partiell aktivering av p53s utmognads-vŠgar Šr tillrŠcklig fšr att fŒ leukemiceller att Ómogna sig till dšdsÓ. Vi har ocksŒ visat att p53s fšrmŒga att fŒ leukemiceller att mogna ut Šr delvis oberoende av dess fšrmŒga att tvinga leukemiceller till programmerad celldšd. Eftersom vissa cancerceller Šr resistenta mot p53fšrmedlad celldšd, innebŠr detta att aktivering av p53s utmognadsvŠgar i dessa celler skulle kunna leda till celldšd trots cellernas motstŒndskraft mot p53fšrmedlad celldšd. Dessutom fšrstŠrker p53 utmognads-effekten av andra utmognadsinducerande Šmnen, vilket antyder att aktivering av p53-fšrmedlad utmognad skulle kunna potentiera differentieringsterapi med andra substanser.



Mycket forskning ŒterstŒr innan differentieringsterapi baserad pŒ aktivering av p53beroende utmognadsvŠgar kan bli klinisk verklighet. Dock tyder vŒra resultat pŒ att detta Šr en lovande framtida behandlingsmšjlighet vid akut leukemi. (Less)
Abstract
The terminal differentiation of leukemic cells is closely connected to their death. The concept of differentiation therapy originates from the idea that forced maturation of leukemic cells could induce cell death without the side-effects that are provoked by ordinary chemotherapy. The tumour suppressor protein p53 is a transcription factor, and can induce cell cycle arrest and apoptosis of malignant cells. Importantly, p53 is also known to induce differentiation in many different tissues including leukemic cells. Thus, to restore p53-dependent pathways for differentiation is an attractive approach in the development of a functional differentiation therapy. However, further knowledge is necessary in order to realise such a concept.... (More)
The terminal differentiation of leukemic cells is closely connected to their death. The concept of differentiation therapy originates from the idea that forced maturation of leukemic cells could induce cell death without the side-effects that are provoked by ordinary chemotherapy. The tumour suppressor protein p53 is a transcription factor, and can induce cell cycle arrest and apoptosis of malignant cells. Importantly, p53 is also known to induce differentiation in many different tissues including leukemic cells. Thus, to restore p53-dependent pathways for differentiation is an attractive approach in the development of a functional differentiation therapy. However, further knowledge is necessary in order to realise such a concept. Therefore, the aim of this thesis was to better understand the pathways for p53-mediated differentiation of leukemic cells. To that end, a temperature inducible p53 mutant (ptsp53) was overexpressed in erythroleukemic K562 cells and monoblastic U-937-4 cells. We show that induced expression of p53 facilitates erythroid but not megakaryocytoid differentiation. Moreover, p53 can induce differentiation of U-937-4 cells in spite of inhibition of p53-mediated apoptosis as mediated by bcl-2. Also, the amount of active p53 seems to determine whether p53 will induce apoptosis or differentiation. In addition, p53-mediated differentiation depends on the transcription regulatory capacity of p53, but the p53 target gene p21 does not seem to be the key molecule mediating p53-induced differentiation. The Wilms tumour protein WT1 binds to p53, modulating its functions. Our data demonstrate that WT1 interferes with the differentiation of monoblastic U-937-4 cells, suggesting that WT1 could have a role in the differentiation block of acute leukemia. In conclusion, our data speak in favour of development of differentiation therapy based on p53-dependent differentiation pathways. (Less)
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author
opponent
  • Assistant professor Grandér, Dan, Institute of Oncology-Pathology, Karolinska Institute, Stockholm
organization
publishing date
type
Thesis
publication status
published
subject
keywords
extracellular fluids, p53-differentiation-p21-WT1-leukemia, Hematologi, Haematology, extracellulära vätskor
pages
170 pages
publisher
Department of Hematology, Lund University
defense location
Segerfalk lecture room, Wallenberg Neurocentre, BMC, Lund
defense date
2001-10-06 09:15
ISBN
91-628-4936-0
language
English
LU publication?
yes
id
f56e2e41-bd70-414c-ba25-ea58833ffff3 (old id 41779)
date added to LUP
2007-08-01 11:44:39
date last changed
2016-09-19 08:45:01
@phdthesis{f56e2e41-bd70-414c-ba25-ea58833ffff3,
  abstract     = {The terminal differentiation of leukemic cells is closely connected to their death. The concept of differentiation therapy originates from the idea that forced maturation of leukemic cells could induce cell death without the side-effects that are provoked by ordinary chemotherapy. The tumour suppressor protein p53 is a transcription factor, and can induce cell cycle arrest and apoptosis of malignant cells. Importantly, p53 is also known to induce differentiation in many different tissues including leukemic cells. Thus, to restore p53-dependent pathways for differentiation is an attractive approach in the development of a functional differentiation therapy. However, further knowledge is necessary in order to realise such a concept. Therefore, the aim of this thesis was to better understand the pathways for p53-mediated differentiation of leukemic cells. To that end, a temperature inducible p53 mutant (ptsp53) was overexpressed in erythroleukemic K562 cells and monoblastic U-937-4 cells. We show that induced expression of p53 facilitates erythroid but not megakaryocytoid differentiation. Moreover, p53 can induce differentiation of U-937-4 cells in spite of inhibition of p53-mediated apoptosis as mediated by bcl-2. Also, the amount of active p53 seems to determine whether p53 will induce apoptosis or differentiation. In addition, p53-mediated differentiation depends on the transcription regulatory capacity of p53, but the p53 target gene p21 does not seem to be the key molecule mediating p53-induced differentiation. The Wilms tumour protein WT1 binds to p53, modulating its functions. Our data demonstrate that WT1 interferes with the differentiation of monoblastic U-937-4 cells, suggesting that WT1 could have a role in the differentiation block of acute leukemia. In conclusion, our data speak in favour of development of differentiation therapy based on p53-dependent differentiation pathways.},
  author       = {Drott, Kristina},
  isbn         = {91-628-4936-0},
  keyword      = {extracellular fluids,p53-differentiation-p21-WT1-leukemia,Hematologi,Haematology,extracellulära vätskor},
  language     = {eng},
  pages        = {170},
  publisher    = {Department of Hematology, Lund University},
  school       = {Lund University},
  title        = {How can p53 induce differentiation of leukemic cells?},
  year         = {2001},
}