MSI2 is required for maintaining activated myelodysplastic syndrome stem cells.
James TaggartTzu-Chieh HoElianna AminHaiming XuTrevor S BarloweAlexendar R PerezBenjamin H DurhamPatrick TivnanRachel OkabeArthur ChowLy VuSun Mi ParkCamila PrietoChristopher FamulareMinal PatelChristopher J LengnerAmit VermaGail RobozMonica GuzmanVirginia M KlimekOmar Abdel-WahabChristina LeslieStephen D NimerMichael Gregory KharasPublished in: Nature communications (2016)
Myelodysplastic syndromes (MDS) are driven by complex genetic and epigenetic alterations. The MSI2 RNA-binding protein has been demonstrated to have a role in acute myeloid leukaemia and stem cell function, but its role in MDS is unknown. Here, we demonstrate that elevated MSI2 expression correlates with poor survival in MDS. Conditional deletion of Msi2 in a mouse model of MDS results in a rapid loss of MDS haematopoietic stem and progenitor cells (HSPCs) and reverses the clinical features of MDS. Inversely, inducible overexpression of MSI2 drives myeloid disease progression. The MDS HSPCs remain dependent on MSI2 expression after disease initiation. Furthermore, MSI2 expression expands and maintains a more activated (G1) MDS HSPC. Gene expression profiling of HSPCs from the MSI2 MDS mice identifies a signature that correlates with poor survival in MDS patients. Overall, we identify a role for MSI2 in MDS representing a therapeutic target in this disease.
Keyphrases
- stem cells
- binding protein
- poor prognosis
- genome wide
- bone marrow
- acute myeloid leukemia
- gene expression
- dna methylation
- dendritic cells
- type diabetes
- metabolic syndrome
- intensive care unit
- immune response
- copy number
- liver failure
- skeletal muscle
- long non coding rna
- prognostic factors
- extracorporeal membrane oxygenation
- adipose tissue
- genome wide analysis