268O - Genetic variations in hematopoietic and mesenchymal stem cells in de novo myelodysplastic syndromes

Background

Myelodysplastic syndromes (MDS) are a bone marrow (BM) stem cell disorders. Studying both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) in MDS marrow is equally important for the proper understanding of the disease pathogenesis. Comparative genetic variation (GV) profiling of HSCs and MSCs in MDS were conducted in the same patient group and between patients of de novo MDS patients of a South Asian cohort.

Methods

DNA was isolated from BM derived HSCs and MSCs from 20 newly diagnosed untreated MDS patients. Next Generation Sequencing was performed using a panel of 54 genes that are commonly mutated in myeloid malignancies. The structural and functional effects of GVs were determined by bioinformatics analysis. A phenotype-genotype correlation was made based on the detected GVs.

Results

The number of mutated genes in HSCs and MSCs were 42 and 38 respectively. The genetic variants identified in HSCs were distinct from that of MSCs. The most frequently mutated genes in both cell types were TET2, KDM6A, BCOR, EZH2 and ASXL. DNA methylation and chromatin remodeling were affected mostly in both cell types. The genetic variations in genes in the cohesion complex and epigenetic mechanisms were shown to co-exist in both cell types. Our cohort carried previously reported variations in myeloid malignancies in HSCs and MSCs . Novel recurrent variants were: KDM6A(c.619 + 6T>A), KMT2A(D2488V), ASXL1(C1182W & V1539G), STAG2(T1124P), BCORL1(V1268G) and IDH1(E47G) in HSCs and DNMT3A(H588P), KIT(H485P), KDM6A(T181P & T833P), ASXL1 (S767P), ETV6 (E327G), BCOR(H1367P) and CBL(E448V) in MSCs. The insertion (E598DYVDFREYE) of the FLT3 gene and the insertion (L287LCX) in the NPM1 gene were co-occurred in 3 patients. Genetic variations in BCORL1 were significantly associated with refractory anaemia.

Conclusions

Altered genome of MSCs supports the hypothesis of a possible role of MSCs in MDS pathogenesis. Detection of distinct variants in HSC and MSC compartments would indicate the genetic variations occur following differentiation into the two cell lineages. The novel recurrent variants identified in the study stand as potential biological markers in diagnosis, prognosis and therapeutic intervention of MDS and needs further study.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

NA.

Funding

University Grants Commission of Sri Lanka and National Science Foundation of Sri Lanka.

Disclosure

All authors have declared no conflicts of interest.