PROJECT SUMMARY

Mutations in the gene DDX41 are the most common inherited cause of MDS predisposition. Patients usually inherit one mutated copy of DDX41 and later acquire a second mutation in blood stem cells. Although these mutations impair proliferation, the mutant stem cells become dominant in the bone marrow through an unknown mechanism.

To understand how this occurs, we performed single cell genetic analyses of blood and bone marrow from patients with DDX41 mutations. Unexpectedly, mutant blood stem cells showed features of both stem cells and dendritic cells, a type of specialized immune cell. This dual identity may explain how mutant stem cells gain a competitive advantage over healthy stem cells without dividing more rapidly. Dendritic cells produce inflammatory signaling proteins, such as interferons, which can deplete healthy blood stem cells when chronically present. We hypothesize that blood stem cells with two DDX41 mutations acquire dendritic cell-like inflammatory functions that damage healthy stem cells, allowing mutant cells to dominate.

In Aim 1, we will determine whether this dendritic cell-like state is common among patients, identify key inflammatory signals, and test their effects in mouse models. In Aim 2, we will define how DDX41 mutations drive dendritic cell gene expression, focusing on direct regulation of the transcription factor SPI B. This project may reveal new therapeutic strategies, including repurposing of available dendritic cell-targeting therapies.