Abstract
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.
Highlights
Myelodysplastic syndromes (MDS) are driven by complex genetic and epigenetic alterations
In our examination of a previously published expression data set, we found that MSI2 expression was increased in CD34 þ population in high-risk MDS patients compared with healthy individuals that were not age matched or Low-Risk MDS (Refractory Anemia; RA or refractory anemia with ringed sideroblasts; RARS), Fig. 1a)[12]
In contrast to the acute myelogenous leukemia (AML) patient data, where elevated MSI2 expression correlates with FLT3-ITD/NPM1 mutations[5,8,9,11], MDS patients do not typically harbour these mutations
Summary
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. The MDS HSPCs remain dependent on MSI2 expression after disease initiation. Gene expression profiling of HSPCs from the MSI2 MDS mice identifies a signature that correlates with poor survival in MDS patients. Recent studies of MSI2 in normal and malignant hematopoietic stem cell (HSC) biology suggested that MSI2 might play a role in myelodysplastic syndromes (MDS)[4,5,6,7,8,9,10,11]. It was previously reported that MSI2 expression in MDS was reduced in patients with low-risk and high-risk MDS compared with normal CD34 cells[7]. We utilize MSI2 loss and gain of function approaches in the context of a mouse model of MDS and find that MSI2 is required for MDS
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