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

Abstract

Key Points• 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.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. (Blood. 2013; 122(3):413-423)

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

“…Mouse strains used for this study and the protocols used for fluorescenceactivated cell sorting (FACS), gene expression analysis, and chromatin immunoprecipitation have been reported previously 33 and are detailed in the supplemental Methods and supplemental Tables 1 and 2 (available on the Blood Web site).…”

“…The MP compartment is also expanded, whereas lymphoid progenitors are nearly absent in Runx1-deficient BM. This latter trait can be traced to crucial functions in initiating the B-cell program 33 and during early stages of T-cell development, 34 but a pivotal function of Runx1 in myeloid-cell fate has not been discerned. Indeed the sole, characterized myeloid defect in Runx1-deficient mice is impaired Meg maturation.…”

“…27,28 Runx1 colocalizes with TFs specific for the HSC/MPP compartment 29 but is also implicated in TF complexes associated with Meg and erythroid (Ery) progenitors, 30,31 granulocyte (G) and/or monocyte (M) progenitors, 32 and cells of the lymphoid compartment. 33,34 To decipher the function and importance of Runx1 within these TF complexes, the consequence of its inactivation has been studied in mouse models. An important finding is the observed three-to eightfold expansion of the LSK population in the absence of Runx1, 33,[35][36][37] suggesting a key function in self-renewal and differentiation decisions.…”

“…33,34 To decipher the function and importance of Runx1 within these TF complexes, the consequence of its inactivation has been studied in mouse models. An important finding is the observed three-to eightfold expansion of the LSK population in the absence of Runx1, 33,[35][36][37] suggesting a key function in self-renewal and differentiation decisions. The MP compartment is also expanded, whereas lymphoid progenitors are nearly absent in Runx1-deficient BM.…”

The RUNX1–PU.1 axis in the control of hematopoiesis

“…RUNX1 also suppresses the emergence of regulatory T-cells (Treg) by inhibiting the expression of FOXP3 [80,81]. In B-cells, the expression of RUNX1 and its binding to enhancer regions of critical pre-B cell transition genes are required for the production and survival of early B-cell progenitors [82]. Early B-cell development is also facilitated by enhanced expression of Ebf1 via the RUNX1-CBFβ interaction [83].…”