LMO2 is essential to maintain the ability of progenitors to differentiate into T-cell lineage in mice

Abstract

Notch signaling primarily determines T-cell fate. However, the molecular mechanisms underlying the maintenance of T-lineage potential in pre-thymic progenitors remain unclear. Here, we established two murine <i>Ebf1</i>-deficient pro-B cell lines, with and without T-lineage potential. The latter expressed lower levels of <i>Lmo2</i>; their potential was restored via ectopic expression of <i>Lmo2</i>. Conversely, the CRISPR/Cas9-mediated deletion of <i>Lmo2</i> resulted in the loss of the T-lineage potential. Introduction of <i>Bcl2</i> rescued massive cell death of Notch-stimulated pro-B cells without efficient LMO2-driven <i>Bcl11a</i> expression but was not sufficient to retain their T-lineage potential. Pro-B cells without T-lineage potential failed to activate <i>Tcf7</i> due to DNA methylation; <i>Tcf7</i> transduction restored this capacity. Moreover, direct binding of LMO2 to the <i>Bcl11a</i> and <i>Tcf7</i> loci was observed. Altogether, our results highlight LMO2 as a crucial player in the survival and maintenance of T-lineage potential in T-cell progenitors via the regulation of the expression of <i>Bcl11a</i> and <i>Tcf7</i>.