Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes

Area of Science:

• Hematology
• Cancer Genetics
• Stem Cell Biology

Background:

• Myeloid neoplasms, such as myelodysplastic syndromes (MDS), are driven by acquired mutations in hematopoietic stem and progenitor cells (HPCs).
• The sequence and functional impact of these mutations on HPCs are not fully understood.
• Understanding clonal evolution is crucial for deciphering MDS pathogenesis.

Purpose of the Study:

• To determine the temporal order of premalignant mutations in MDS.
• To investigate the functional consequences of clonal evolution on hematopoietic differentiation.
• To identify key molecular pathways affected during MDS progression.

Main Methods:

• Episomal reprogramming of MDS patient samples to generate induced pluripotent stem cells (iPSCs) from single premalignant cells.
• Differentiation of isogenic MDS iPSCs with defined mutational landscapes.
• Analysis of mitochondrial function, genome stability, and hematopoietic differentiation potential.

Main Results:

• Reprogramming preferentially isolated early subclones with fewer mutations, enabling reconstruction of mutation order.
• Isogenic MDS iPSCs showed progressive loss of hematopoietic differentiation potential with increasing mutations.
• SF3B1 and epigenetic mutations impaired mitochondrial function, leading to ineffective erythropoiesis.
• 5q deletion was identified as an early event cooperating with TP53 mutations to destabilize the genome.

Conclusions:

• Episomal reprogramming is a powerful tool for studying preleukemic clonal evolution in MDS.
• Mitochondrial dysfunction and compromised genome stability are critical pathways in MDS pathogenesis.
• Elucidating mutation order provides insights into the stepwise development of myeloid neoplasms.