title: Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.
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 ofIKZF1deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses ofBTG1were significantly enriched inIKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0.007). WhileBTG1deletions alone had no impact on prognosis, the combined presence ofBTG1andIKZF1deletions 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 withIKZF1-deleted cases withoutBTG1aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such asCDKN2A/B, PAX5, EBF1orRB1, did not affect the outcome ofIKZF1-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 anIkzf1heterozygous background. We observed that loss ofBtg1increased the tumor incidence ofIkzf1+/-mice in a dose-dependent manner. Moreover, murine B cells deficient forBtg1andIkzf1+/-displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identifyBTG1as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse inIKZF1-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.
authors.affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands blanca.scheijen@radboudumc.nl.
authors.forename: Blanca
authors.initials: B
authors.lastname: Scheijen
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Marke
authors.affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Tijchon
authors.affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Dorette
authors.initials: D
authors.lastname: van Ingen Schenau
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands.|Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Esmé
authors.initials: E
authors.lastname: Waanders
authors.affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Emst
authors.affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Laurens T
authors.initials: LT
authors.lastname: van der Meer
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Research Institute Children's Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Escherich
authors.affiliation: Research Institute Children's Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Horstmann
authors.affiliation: Dutch Childhood Oncology Group, The Hague, the Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.affiliation: Australian and New Zealand Children's Oncology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Venn
authors.affiliation: Australian and New Zealand Children's Oncology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sutton
authors.affiliation: Oncology Unit, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Luciano
authors.initials: L
authors.lastname: Dalla-Pozza
authors.affiliation: Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands.|Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
mesh_terms: D000293:Adolescent; D000818:Animals; D014408:Biomarkers, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D063868:Patient Outcome Assessment; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012008:Recurrence; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C497239:IKZF1 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; C074086:BTG1 protein, human; D051740:Ikaros Transcription Factor