Therapeutic discovery for marrow failure with MDS predisposition using pluripotent stem cells

Area of Science:

• Hematology
• Genetics
• Stem Cell Biology

Background:

• Monosomy 7 or deletion of 7q (del(7q)) are common in high-grade myelodysplastic syndromes (MDS).
• Treatments for bone marrow failure can inadvertently stimulate clonal outgrowth.
• Shwachman Diamond Syndrome (SDS) is a bone marrow failure disorder with MDS predisposition.

Purpose of the Study:

• To investigate the biological impact of del(7q) in the context of bone marrow failure.
• To explore therapeutic strategies for MDS arising in inherited bone marrow failure syndromes.

Main Methods:

• Generated induced pluripotent stem cells (iPSCs) from SDS patients.
• Genomically engineered a 7q deletion in SDS-derived iPSCs (SDSdel(7q)).
• Performed transcriptomic analysis and measured SMAD2 phosphorylation to assess TGFβ pathway activity.

Main Results:

• The TGFβ pathway was significantly altered in SDS versus SDSdel(7q) iPSCs.
• SMAD2 phosphorylation, indicating TGFβ pathway activation, was reduced by 7q deletion.
• TGFβ pathway inhibition rescued hematopoiesis in SDS iPSCs and patient cells, but not in SDSdel(7q) cells.

Conclusions:

• Inhibition of the TGFβ pathway represents a potential therapeutic target to improve hematopoiesis in SDS.
• The germline context of somatic alterations is crucial for developing precision medicine approaches for MDS.