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CLS Journal Club 5

Submitted by imkhan on 15 May 2022

Abstract: Myelodysplastic syndromes (MDS) are a heterogeneous group of age-associated hematopoietic diseases characterised by abnormal blood cell maturation and a high propensity for leukemic transformation. It is a clonal disease thought to originate in the haematopoietic stem cell (HSC). Therapeutic strategies in high-risk patients include demethylating agents and cytotoxic drugs,
however, 50-60% of these patients do not respond to the treatment and progress to the worst stage. Therefore, there is an unmet clinical need to better understand the mechanisms leading to these
blood disorders with the ultimate aim to facilitate the development of improved diagnostic and therapeutic strategies. By making use of somatic reprogramming and CRISPR-Cas9 tools, our goal in
this study was to generate an in vitro model of low-risk and high-risk MDS that could help to determine the molecular mechanisms leading to disease progression. To generate a model for highrisk
MDS, a mutation in C/EBPα causing disruption of the DNA binding domain was generated by CRISPR in the MDS27-iPSC cells, mimicking the additional mutation observed in MDS27 cells when
the patient progressed to high-risk MDS. The differentiation of the C/EBPα mutant line (high-risk MDS-iPSC) showed a significant reduction in the myeloid and erythroid colony forming units (CFUs)
with a block in granulocytic CFU formation. Furthermore, study of the myeloid lineage indicated that the high-risk MDS-iPSC had an impaired myeloid differentiation due to altered expression of key
genes required for myeloid differentiation such as PU.1, GATA2, LMO2 and RUNX1. The study of the erythroid lineage in high-risk MDS27 indicated that the four mutant genes induce erythroid
differentiation, increasing the aberrant morphology. Our approach highlights the utility of human iPSCs to understand the molecular mechanisms leading to disease progression and their use as a
platform for drug screening which will help to improve diagnostic and therapeutic strategies.