When splicing fails, hematopoiesis collapses.

Pre-mRNA splicing is a foundational step in gene expression. U2AF1 is a small subunit of the U2 auxiliary factor that recognizes the 3' splice site of introns; without correct recognition, splice junctions fail and aberrant transcripts result. Mutations in U2AF1 (most commonly S34F and Q157R) are recurrent in MDS, secondary AML, and some MPN.

The lab's conditional U2af1 knockout shows that the gene is essential for hematopoiesis. Loss produces pancytopenia, hematopoietic stem and progenitor cell ablation, bone marrow failure, and early lethality. The phenotype establishes U2AF1 as a non-redundant requirement for blood-cell production.

To model the disease itself, the lab built a conditional U2AF1-Q157R knock-in mouse — expressing the most common patient mutation at endogenous levels. The animals develop macrocytic anemia and erythroid dysplasia (the morphological hallmarks of MDS) along with stem-cell expansion, recapitulating key clinical features.

Mechanistically, the leading model is that mutant U2AF1 mis-recognizes 3' splice sites, producing aberrant transcripts of genes involved in cell cycle, DNA repair, and stem-cell maintenance. The downstream consequences — replication stress, DNA damage response activation, progenitor attrition — converge on the dysplastic phenotype. SRSF2, another splicing factor mutated in MDS, modifies JAK2V617F MPN by reducing erythrocytosis and impairing progenitor function, suggesting the splicing axis intersects with the MPN program too.