PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function

Area of Science:

• Hematology
• Molecular Biology
• Stem Cell Biology

Background:

• The Mds1 and Evi1 complex locus (Mecom) produces multiple transcripts, some linked to leukemia.
• The role of Mecom-derived gene products in normal hematopoiesis is not well understood.

Purpose of the Study:

• To investigate the function of the upstream transcription start site of Mecom in adult hematopoiesis.
• To elucidate the role of the Mds1-Evi1 (ME) isoform in hematopoietic stem cell (HSC) regulation.

Main Methods:

• Created a mouse model (ME(m1)) with a lacZ knock-in to eliminate the ME isoform.
• Utilized β-galactosidase-marking studies to track ME expression in hematopoietic cells.
• Performed RNA-sequencing on hematopoietic stem cells (LSKs) from ME(m1) mice.

Main Results:

• ME is exclusively expressed in the stem cell compartment of hematopoietic cells.
• ME deficiency reduces HSC numbers, impairs long-term repopulation, and shifts stem cells from quiescence to cycling.
• ME deficiency leads to near-complete silencing of Cdkn1c (p57-Kip2), a negative cell-cycle regulator.
• ME preferentially rescues long-term HSC defects compared to other isoforms.

Conclusions:

• The PR-domain-containing ME isoform is critical for maintaining HSC function and quiescence.
• ME regulates HSC growth control by modulating p57-Kip2 expression.
• ME plays a vital role in normal adult hematopoiesis.