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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)541-551
Aantal pagina's11
TijdschriftHaematologica
Volume102
Nummer van het tijdschrift3
DOI's
StatusGepubliceerd - mrt. 2017

Vingerafdruk

Duik in de onderzoeksthema's van 'Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients'. Samen vormen ze een unieke vingerafdruk.

Citeer dit