The clonal origins of leukemic progression of myelodysplasia

Abstract

The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.

Mutation status and burden can improve prognostic prediction of patients with lower‐risk myelodysplastic syndromes

“…We also observed that LR‐MDS patients with IDH2 mutations were more likely to develop sAML, as previous studies of unselected MDS reported . Mutations of genes involved in DNA methylation including IDH2 might represent early events in MDS and play an indirect role in disease progression through a multistep evolutionary process . NARS mutations were reported to be associated with leukemic transformation of MDS in several studies of serial sequences .…”

“…Mutations of genes involved in DNA methylation including IDH2 might represent early events in MDS and play an indirect role in disease progression through a multistep evolutionary process . NARS mutations were reported to be associated with leukemic transformation of MDS in several studies of serial sequences . However, we failed to statistically find their relation in our study probably because the association was not obvious in the early stage of MDS.…”

Somatic SETBP1 mutations in myeloid neoplasms

“…In addition to functional significance, recent sequencing technology also uncovered clonal dynamics based on detailed information of mutated clone size. In particular, multiple samples tested at serial time points in each case can conclude acquisition timing of each mutation, clonal architecture, and intratumor heterogeneity in myelodysplasia [4,[17][18][19][20].…”

A genetic development route analysis on MDS subset carrying initial epigenetic gene mutations

“…Several in-depth studies have been completed to clarify the detailed mechanism underlying high-frequency mutations (such as SRSF2, ASXL1 and U2AF1) [4][5][6] . In addition, some hematologists are conducting longitudinal (over time) observation of evolutionary models of gene mutation in individual or groups of MDS patients to understand the onset and development of this disease [7][8][9] .…”