Co-occurrence of cohesin complex and Ras signaling mutations during progression from myelodysplastic syndromes to secondary acute myeloid leukemia

Abstract

Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. In order to elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next-generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic transformation. The study showed that MDS progression to sAML is characterized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing ( STAG2 ) and newlyacquired ( NRAS and FLT3 ) mutations. Moreover, we observed co-operation between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their progression to sAML.

Myelodysplastic syndromes: Biological and therapeutic consequences of the evolving molecular aberrations landscape

“…a cooperation between genes involved in the cohesin and RAS pathways was observed in 15% − 20% of MDS patients who evolved to secondary AML [32] …”

Prognosis in Myelodysplastic Syndromes: The Clinical Challenge of Genomic Integration

“…Though external validation is needed, the authors stated that specific comutation patterns account for clinical heterogeneity within SF3B1 , SRSF2 , and del5q MDS. In addition, acquired mutations may be useful for both anticipating the natural history of the disease at diagnosis, and minimal residual disease assessment and prediction of progression during the course of MDS [ 64 , 65 , 66 ]. Lastly, the success or failure of emerging targeted therapies (i.e., IDH1 / 2 or spliceosome inhibitors) may accelerate the implementation of new genes in the workup on MDS patients.…”

Novel Approaches to Target Mutant FLT3 Leukaemia

“…Mutations in the FLT3 gene are not restricted to AML. Albeit uncommon in myelodysplastic syndromes (MDS), increased frequencies of FLT3 mutations are associated with MDS progressing to secondary AML [ 70 , 71 ]. FLT3 mutations are in general rare in acute lymphoblastic leukemia (ALL).…”