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Tumor suppressor IKZF1 mediates glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia

Leukemia volume 30, pages 1599–1603 (2016)Cite this article

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Acute lymphoblastic leukemia (ALL) is characterized by the presence of acquired genetic alterations, including chromosomal translocations, gene deletions and mutations, which drive leukemia initiation and maintenance of the leukemic clone.1 In B-cell precursor ALL (BCP-ALL), genetic alterations inactivating the transcription factor IKZF1 (IKAROS) represent a prognostic marker associated with a higher incidence of relapse.2, 3 However, it has not been established whether the loss of IKZF1 function directly impacts the response to chemotherapy. Synthetic glucocorticoids (GCs), such as dexamethasone and prednisolone, are essential drugs in the multi-agent chemotherapy regimens used to treat patients with lymphoid malignancies, including BCP-ALL. It has been established that both in vitro resistance and a poor day 8 response to GCs predict an unfavorable outcome in pediatric ALL.4, 5, 6 However, despite intensive research, it remains poorly understood which gene aberrations contribute to GC resistance in BCP-ALL.

To explore the mechanism underlying this GC resistance phenotype, we performed microarray gene expression analyses comparing Ikzf1+/− B lymphocytes with WT cells. Comparison with the global gene expression signature derived from IKZF1-deleted BCP-ALL patient samples showed a minimal overlap (Supplementary Figure S4). Ingenuity upstream regulator analyses revealed a dexamethasone-related signature in both untreated and prednisolone-treated B cells (Supplementary Figure S5, Supplementary Table S1), indicating that GC-regulated target genes were differentially expressed in Ikzf1+/− B cells. Indeed, the level of gene induction of 769 prednisolone-activated genes in Ikzf1+/− B lymphocytes was significantly lower compared with the WT cells (P<0.001; Figure 1c, left panel). Similarly, the 774 prednisolone-repressed genes showed a significantly impaired transcriptional response to GCs in Ikzf1+/− B lymphocytes compared with controls (P<0.001; Figure 1c, right panel). To further investigate the expression of individual GC-responsive genes, quantitative reverse transcription PCR was performed for seven genes activated by GCs. The transcriptional response of Tsc22d3, Dusp1, Irs2 and Zfp36l2 was significantly attenuated by Ikzf1 haplodeficiency (Figure 1d), whereas three other GC-activated genes (Sgk1, Ddit4 and Fkbp5) were not differentially regulated in response to prednisolone (Supplementary Figure S6). All four GC-repressed target genes examined (Il1a, Il1b, Sdpr and Il6) displayed a lower basal level of expression in Ikzf1+/− B lymphocytes, of which only one (Il1a) displayed an attenuated response to prednisolone. (Figure 1d).

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Acknowledgements

We thank Meinrad Busslinger for providing us with the Ikzf1Neo mice and William Carroll for the UOCB1 cell line. This study was funded by the KiKa foundation (Stichting Kinderen Kankervrij; Grants 2009-55, 2010-77), in part by the Dutch Cancer Society (KWF grants KUN2009-4298 to RPK and KUN2012-5366 to EW) and the Stichting KOC Nijmegen.

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Author notes

  1. R Marke, J Havinga, F N van Leeuwen and B Scheijen: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Pediatric Oncology, Radboud University Medical Center, Nijmegen, The Netherlands

    R Marke, J Havinga, M Demkes, L Yuniati, D van Ingen Schenau, F N van Leeuwen & B Scheijen

  2. Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands

    J Cloos & G J L Kaspers

  3. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands

    J Cloos

  4. Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    G Poelmans, E Waanders & R P Kuiper

  5. Department of Cognitive Neuroscience, Radboud University, Nijmegen, The Netherlands

    G Poelmans

  6. Department of Molecular Animal Physiology, Radboud University, Nijmegen, The Netherlands

    G Poelmans

  7. Dutch Childhood Oncology Group, The Hague, The Netherlands

    E Sonneveld

  8. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    R Pieters & P M Hoogerbrugge

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  1. R Marke
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Correspondence to B Scheijen.

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Marke, R., Havinga, J., Cloos, J. et al. Tumor suppressor IKZF1 mediates glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia. Leukemia 30, 1599–1603 (2016). https://doi.org/10.1038/leu.2015.359

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