PRR14L

PRR14L is a scaffold protein that bridges the PP2A-B56 phosphatase complex to the spindle assembly factor TACC3, thereby regulating mitotic fidelity; its loss prolongs spindle assembly checkpoint (SAC)-dependent mitotic arrest and sensitizes cells to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors (PMID:41279925). In hematopoietic progenitors, PRR14L knockdown skews differentiation toward monocytes at the expense of neutrophils, recapitulating features of chronic myelomonocytic leukemia (CMML), and RNA-Seq analysis implicates PRR14L in cell division programs (PMID:30573780).

1. 2018 Medium

   Whether PRR14L has a functional role in hematopoiesis was unknown; shRNA knockdown in CD34+ progenitors established that PRR14L loss shifts myeloid differentiation toward monocytes and away from neutrophils, linking it to a CMML-like phenotype and implicating it in cell division.

   Evidence shRNA knockdown in human CD34+ cells with in vitro differentiation assay, RNA-Seq, and cellular localization studies

   PMID:30573780

   Open questions at the time

   • Mechanism by which PRR14L loss alters differentiation balance is undefined
   • No direct interacting partners identified at this stage
   • In vivo validation of the hematopoietic phenotype is lacking
2. 2025 Medium

   The molecular mechanism of PRR14L in mitosis was unresolved; proximity labeling and genome-wide CRISPR screening identified PRR14L as a scaffold connecting PP2A-B56 to TACC3 and showed that its loss deregulates spindle assembly checkpoint dynamics, positioning PRR14L as a mitotic fidelity factor upstream of MPS1-dependent signaling.

   Evidence TurboID proximity labeling and genome-wide CRISPR/Cas9 loss-of-function screen with MPS1 inhibitor in human cell lines (preprint)

   PMID:41279925

   Open questions at the time

   • Preprint; not yet peer-reviewed or independently replicated
   • Direct biochemical reconstitution of the PRR14L–PP2A-B56–TACC3 ternary complex has not been performed
   • Whether the mitotic scaffolding function accounts for the hematopoietic differentiation phenotype is untested

• How PRR14L's mitotic scaffolding role mechanistically connects to its hematopoietic differentiation function, and whether its loss drives clonal hematopoiesis through mitotic error accumulation, remain open questions.
• No in vivo genetic model linking mitotic fidelity defects to myeloid skewing
• Structural basis of PRR14L interaction with PP2A-B56 and TACC3 is unknown
• No patient-derived mutation functional studies connecting specific PRR14L variants to disease phenotype