Kevin Rouault-Pierre’s team – Stress Integration in Normal and Malignant Hematopoietic Stem Cells

Aberrant splicing in MDS leads to the continuous production of abnormal transcripts and proteins, generating chronic proteotoxic stress. However, the mechanisms by which hematopoietic stem cells harboring splicing mutations tolerate and adapt to this stress remain poorly understood.

This program investigates how proteostasis networks are remodeled in normal and mutant hematopoietic stem cells. Building on previous work, from our lab and others, demonstrating the sensitivity of hematopoietic stem and progenitor cells to endoplasmic reticulum stress, it integrates RNA splicing analyses with functional approaches in primary human cells.

This approach enables the identification of stress adaptation pathways that are specifically required by mutant clones while remaining dispensable for normal stem cells. It thereby defines therapeutically exploitable proteostasis vulnerabilities and provides a mechanistic framework to understand inter-patient heterogeneity in disease progression and treatment responses.

This program explores how the high burden of transcripts sensitive to nonsense-mediated decay (NMD) in MDS with splicing factor mutations can be exploited to induce synthetic lethality. It builds on the observation that modulating the translation of these aberrant transcripts exacerbates proteotoxic stress and disrupts protein quality control systems in mutant cells.

By combining functional approaches with integrated genomic analyses in both mutant and non-mutant myeloid models, this program aims to identify specific molecular dependencies that emerge under conditions of heightened protein stress.

These studies will define selective vulnerabilities of clones harboring splicing alterations while sparing normal cells. Ultimately, this work provides a rational framework for the development of combination therapeutic strategies that preferentially target mutant cells and supports the emergence of new preclinical approaches in MDS and other diseases associated with splicing factor mutations.