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Het voorspellen van de gevoeligheid van kinderleukemiecellen voor proteasoomremmers

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Tijdschrift voor Kindergeneeskunde

Samenvatting

Inleiding

Voor kinderen met een recidief na een eerste succesvolle behandeling van acute lymfatische leukemie (ALL) en acute myeloïde leukemie (AML) bestaat een grote behoefte aan nieuwe geneesmiddelen. Bortezomib (BTZ) is een reversibele proteasoomremmer die momenteel getest wordt in klinische studies bij kinderen met recidief-ALL en -AML. Omdat toxiciteit en resistentie tegen BTZ kunnen optreden, zijn nieuwe proteasoomremmers ontwikkeld. Het doel van dit onderzoek is om te bekijken of kinderleukemiecellen gevoelig zijn voor BTZ en proteasoomremmers van de tweede generatie (carfilzomib, ONX 0912 en ONX 0914), en om factoren te identificeren die voorspellen hoe een kind zal reageren op behandeling met proteasoomremmers.

Methoden

Voor leukemische blastcellen van 29 ALL- en 10 AML-patiënten werden de gevoeligheden voor BTZ, carfilzomib, ONX 0912, ONX 0914 en het glucocorticoïd dexamethason bepaald met de MTT-celviabiliteitstest. Daarnaast werd de eiwitexpressie van de functioneel-actieve proteasoomsubunits bepaald met western blot en ProCISE, en gecorreleerd aan de gevoeligheid voor proteasoomremmers.

Resultaten

ALL-cellen waren significant gevoeliger voor alle proteasoomremmers en dexamethason dan AML-cellen. Expressie van de constitutieve proteasoomsubunits ten opzichte van immuunproteasoomsubunits was significant hoger in AML-cellen dan in ALL-cellen. De ratio van immuun-/constitutieve proteasoomsubunits bleek goed te correleren met de gevoeligheid van ALL-cellen voor ONX 0914 en AML-cellen voor BTZ en carfilzomib.

Conclusie

Expressieniveaus van proteasoomsubunits kunnen van voorspellende waarde zijn hoe een kind zal reageren op proteasoomremmers. Hiermee draagt dit onderzoek bij aan een gerichtere behandeling van kinderen met leukemie.

Summary

Introduction

For children with relapsed acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), there is a need for new therapeutic drugs. Bortezomib (BTZ) is a reversible proteasome inhibitor currently being tested in clinical trials for children with relapsed ALL and AML. BTZ-related toxicity and emergence of resistance has initiated the development of several new irreversible proteasome inhibitors. The aim of this research project is to investigate whether pediatric leukemia cells are sensitive to BTZ and new generation proteasome inhibitors (carfilzomib, ONX 0912 and ONX 0914), and to identify factors that will predict responsiveness of children on treatment with proteasome inhibitors.

Methods

Leukemic blast cells of 29 ALL and 10 AML patients were analyzed for sensitivity to BTZ, carfilzomib, ONX 0912, ONX 0914, and the glucocorticoid dexamethasone by MTT cytotoxicity assays. Additionally, protein expression of the functionally-active proteasome subunits was determined by Western blotting and ProCISE, and correlated to proteasome inhibitor sensitivity.

Results

ALL cells were significantly more sensitive to all proteasome inhibitors and dexamethasone than AML cells. Besides this, expression of constitutive proteasome subunits relative to immune proteasome subunits was significantly higher in AML cells than in ALL cells. The ratio of immune/constitutive proteasome subunit expression correlated with sensitivity of ALL cells for ONX 0914, and of AML for BTZ and carfilzomib sensitivity.

Conclusion

Expression levels of proteasome subunits can be of predictive value how a patient may respond to proteasome inhibitors. As such, this research contributes to a more personalized therapy for children with leukemia in the future.

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Author information

Authors and Affiliations

  1. afdeling Kinderoncologie/Hematologie, VUmc, De Boelelaan 1117, 1081, HV, Amsterdam, The Netherlands

    G.J.L. Kaspers

  2. afdeling Kinderoncologie/Hematologie, VU medisch centrum, Amsterdam, The Netherlands

    D. Niewerth &  N.E. Franke

  3. afdeling Reumatologie, VU medisch centrum, Amsterdam, The Netherlands

    G. Jansen

  4. afdelingen Kinderoncologie/Hematologie en Hematologie, VU medisch centrum, Amsterdam, The Netherlands

    J. van Meerloo &  J. Cloos

  5. afdeling Hematologie, VU medisch centrum, Amsterdam, The Netherlands

    S. Zweegman

  6. Stichting Kinderoncologie Nederland, Den Haag, The Netherlands

    V. de Haas

Authors
  1. D. Niewerth
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  2. N.E. Franke
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  3. G. Jansen
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  4. J. van Meerloo
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  5. S. Zweegman
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  6. V. de Haas
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  7. J. Cloos
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  8. G.J.L. Kaspers
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Corresponding author

Correspondence to G.J.L. Kaspers.

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Auteurs

Mw. Denise Niewerth, dhr. Niels E. Franke en dhr. prof.dr. Gertjan J.L. Kaspers, afdeling Kinderoncologie/ Hematologie; dhr. dr. Gerrit Jansen, afdeling Reumatologie; dhr. Johan van Meerloo en mw. dr. Jacqueline Cloos, afdelingen Kinderoncologie/Hematologie en Hematologie; mw. prof.dr. Sonja Zweegman, afdeling Hematologie, VU medisch centrum, Amsterdam. Mw. dr. Valerie de Haas, Stichting Kinderoncologie Nederland, Den Haag. Correspondentieadres: Prof.dr. G.J.L. Kaspers, afdeling Kinderoncologie/Hematologie, VUmc, De Boelelaan 1117, 1081 HV Amsterdam, gjl.kaspers@ vumc.nl.

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Niewerth, D., Franke, N., Jansen, G. et al. Het voorspellen van de gevoeligheid van kinderleukemiecellen voor proteasoomremmers. TIJDSCHR. KINDERGENEESKUNDE 82, 79–88 (2014). https://doi.org/10.1007/s12456-014-0014-9

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  • DOI: https://doi.org/10.1007/s12456-014-0014-9

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