Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients

Blanca Scheijen, Judith M Boer, René Marke, Esther Tijchon, Dorette van Ingen Schenau, Esmé Waanders, Liesbeth van Emst, Laurens T van der Meer, Rob Pieters, Gabriele Escherich, Martin A Horstmann, Edwin Sonneveld, Nicola Venn, Rosemary Sutton, Luciano Dalla-Pozza, Roland P Kuiper, Peter M Hoogerbrugge, Monique L den Boer, Frank N van Leeuwen

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival (P=0.0003) and a higher 5-year cumulative incidence of relapse (P=0.005), when compared with IKZF1-deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1, did not affect the outcome of IKZF1-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1-deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1+/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1+/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.

Original languageEnglish
Pages (from-to)541-551
Number of pages11
JournalHaematologica
Volume102
Issue number3
DOIs
Publication statusPublished - Mar 2017

Keywords

  • Adolescent
  • Animals
  • Biomarkers, Tumor
  • Cell Transformation, Neoplastic/genetics
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Drug Resistance, Neoplasm/genetics
  • Epistasis, Genetic
  • Female
  • Gene Deletion
  • Genetic Predisposition to Disease
  • Humans
  • Ikaros Transcription Factor/genetics
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins/genetics
  • Patient Outcome Assessment
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
  • Prognosis
  • Recurrence
  • Tumor Suppressor Proteins/genetics

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