title: Runx1 is essential at two stages of early murine B-cell development.
abstract: The t(12;21) chromosomal translocation, targeting the gene encoding the RUNX1 transcription factor, is observed in 25% of pediatric acute lymphoblastic leukemia (ALL) and is an initiating event in the disease. To elucidate the mechanism by which RUNX1 disruption initiates leukemogenesis, we investigated its normal role in murine B-cell development. This study revealed 2 critical functions of Runx1: (1) to promote survival and development of progenitors specified to the B-cell lineage, a function that can be substituted by ectopic Bcl2 expression, and (2) to enable the developmental transition through the pre-B stage triggered by the pre-B-cell antigen receptor (pre-BCR). Gene expression analysis and genomewide Runx1 occupancy studies support the hypothesis that Runx1 reinforces the transcription factor network governing early B-cell survival and development and specifically regulates genes encoding members of the Lyn kinase subfamily (key integrators of interleukin-7 and pre-BCR signaling) and the stage-specific transcription factors SpiB and Aiolos (critical downstream effectors of pre-BCR signaling). Interrogation of expression databases of 257 ALL samples demonstrated the specific down-regulation of the SPIB and IKZF3 genes (the latter encoding AIOLOS) in t(12;21) ALL, providing novel insight into the mechanism by which the translocation blocks B-cell development and promotes leukemia.
authors.affiliation: Molecular Pathology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, Hamburg, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Niebuhr
authors.forename: Neele
authors.initials: N
authors.lastname: Kriebitzsch
authors.forename: Meike
authors.initials: M
authors.lastname: Fischer
authors.forename: Kira
authors.initials: K
authors.lastname: Behrens
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.forename: Ulla
authors.initials: U
authors.lastname: Bergholz
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller
authors.forename: Susanne
authors.initials: S
authors.lastname: Roscher
authors.forename: Marion
authors.initials: M
authors.lastname: Ziegler
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
authors.forename: Adam
authors.initials: A
authors.lastname: Grundhoff
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D001665:Binding Sites; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D015973:Gene Expression Regulation, Leukemic; D018390:Gene Targeting; D016678:Genome / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor; D051379:Mice; D008810:Mice, Inbred C57BL; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C491396:Ikzf3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C493726:Runx1 protein, mouse; D015534:Trans-Activators; D051740:Ikaros Transcription Factor