Role of nuclear architecture in MDS/AML carcinogenesis and chemoresistance

Myelodysplastic Syndrome (MDS) patients with defective neutrophils (PMN) are at significantly higher risk to progress towards an aggressive, life-threatening Acute Myeloid Leukaemia (AML). Previously, we demonstrated that pathological increase in PMN-derived miR-23a promotes carcinogenesis in surrounding cells due to miR-23a mediated down regulation of nuclear envelope protein Lamin B1 (LB1), a key regulator of genome integrity and chromosomal stability. Importantly, it’s established that LB1 is crucial for maturation of hematopoietic stem cells, while increase in miR-23a exacerbate AML and its severity. Surprisingly, despite this established knowledge, little is known about the role of LB1 in MDS/AML carcinogenesis and chemoresistance. Thus, we study the contribution of PMN-miR-23a-LB1 axis to rapid MDS -AML progression associating with pathogenetic changes in genome landscape and chromosomal stability.

Dedicated screening utilizing cell populations and cytological analyzes of patients’ bone marrow aspirates (BMA), identified MDS/AML specimens with pathological PMN presentation and cancerous cells with severe nuclear architecture and structure deformities, one of the hallmarks of chromosomal instability. Next, these BMAs have been subjected to targeted miR-23a and LB1 expression analyses, advanced Optical Genome Mapping (OGM) and New Generation Sequencing (NGS) profiling to correlate their pathological phenotype with recurrent chromosomal aberrations and gene-specific biomarkers.

In summary, we suggest that clinical miR-23ahigh/LB1low MDS specimens harbor unique pathogenetic chromosomal landscape and genome mutational signature enabling aggressive carcinogenesis, increased heterogeneity and chemoresistance. Importantly, this allow us to develop improved diagnostic and prognostic tools for patients that are at high risk to develop aggressive and chemoresistant AML and identify novel therapeutic targets.