Runx1 is essential at two stages of early murine B-cell development

• Published in: Blood Vol. 122; no. 3; pp. 413 - 423
• Main Authors: Niebuhr, Birte, Kriebitzsch, Neele, Fischer, Meike, Behrens, Kira, Günther, Thomas, Alawi, Malik, Bergholz, Ulla, Müller, Ursula, Roscher, Susanne, Ziegler, Marion, Buchholz, Frank, Grundhoff, Adam, Stocking, Carol
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.07.2013
• Subjects: Animals; Apoptosis - genetics; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Binding Sites; Cell Differentiation - immunology; Cell Lineage - genetics; Cell Lineage - immunology; Cell Proliferation; Cell Survival - genetics; Cell Survival - immunology; Chromosomes, Human, Pair 12 - genetics; Chromosomes, Human, Pair 21 - genetics; Core Binding Factor Alpha 2 Subunit - deficiency; Core Binding Factor Alpha 2 Subunit - metabolism; Enhancer Elements, Genetic - genetics; Gene Deletion; Gene Expression Regulation, Developmental; Gene Expression Regulation, Leukemic; Gene Targeting; Genome - genetics; Humans; Ikaros Transcription Factor; Mice; Mice, Inbred C57BL; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Protein Binding - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Translocation, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-01-480244

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. •Runx1 is necessary for survival and development of B cell–specified progenitors and also the transition through the pre-B-cell stage.•Genomewide expression and Runx1 occupancy analyses identified critical target genes and collaborating transcription partners.