Runx1 is essential at two stages of early murine B-cell development.
Blood, 2013/7/18;122(3):413-23.
Niebuhr B[1], Kriebitzsch N, Fischer M, Behrens K, Günther T, Alawi M, Bergholz U, Müller U, Roscher S, Ziegler M, Buchholz F, Grundhoff A, Stocking C
Affiliations
PMID: 23704093DOI: 10.1182/blood-2013-01-480244
Impact factor: 25.476
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.
MeSH terms
Animals; Apoptosis; B-Lymphocytes; Binding Sites; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Survival; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 21; Core Binding Factor Alpha 2 Subunit; Enhancer Elements, Genetic; Gene Deletion; Gene Expression Regulation, Developmental; Gene Expression Regulation, Leukemic; Gene Targeting; Genome; Humans; Ikaros Transcription Factor; Mice; Mice, Inbred C57BL; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Trans-Activators; Translocation, Genetic
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