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

Blood. 2013 Jul 18;122(3):413-23. doi: 10.1182/blood-2013-01-480244. Epub 2013 May 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Core Binding Factor Alpha 2 Subunit
  • Ikzf3 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Runx1 protein, mouse
  • Trans-Activators
  • Ikaros Transcription Factor