RNA binding proteins Pcbp1 and Pcbp2 are indispensable for B cell development [scRNA-seq]

Here, we identify the RNA-binding proteins Pcbp1 and Pcbp2 as essential, redundant regulators of early B lymphopoiesis. While a single deficiency of either Pcbp1 or Pcbp2 results in only a partial blockade at the pro-B to pre-B transition, their combined deletion causes a near-complete arrest.

Using single-cell RNA sequencing, we identify the developmental bottleneck to the pro-B VDJ A stage—characterized by active D-JH rearrangement—with a failure to generate Lambda pre-B or immature B cells. Mechanistically, Pcbp1/2 deficiency triggers multifaceted cell-intrinsic defects: loss of Ebf1-driven lineage identity, mitochondrial dysfunction, and accumulation of proteotoxic stress. These defects converge to block early progenitor survival and expansion, ultimately preventing B cells from progressing beyond the pre-B stage.