GSE127861
Ringsideroblasts in acute myeloid leukemia are associated with adverse risk and result from an abberant heme-metabolism gene program
Ringsideroblasts(RS) emerge as result of aberrant erythroid differentiation leading to excessive mitochondrial iron accumulation. This feature is characteristic for myelodysplastic syndromes with mutations in spliceosome gene SF3B1. However, RS can also be observed in patients diagnosed with acute myeloid leukemia (AML). The objective of this study was to characterize the presence of RS in a cohort of 109 AML and 17 high-risk MDS patients. Clinically, RS-AML is enriched for ELN adverse-risk (55%). In line with this finding, 35% of all cases had complex cytogenetic aberrancies and TP53 was most recurrently mutated in this cohort (42%), followed by DNMT3A (29%), RUNX1 (21%) and ASXL1 (19%). In contrast to RS-MDS, the incidence of SF3B1 mutations was low (8%). Whole exome sequencing and SNP array analysis on a subset of patients did not uncover one single defect underlying the RS phenotype. Shared genetic defects between erythroblasts and total mononuclear cell fraction indicate common ancestry for the erythroid lineage and the myeloid blast cells in RS-AML patients. Gene expression analysis by performing RNA sequencing on CD34+ AML cells revealed differential gene expression between RS-AML and a separate AML cohort, including genes involved in megakaryocytic/erythroid differentiation and mRNA splicing. Furthermore, several heme-metabolism-related genes were found upregulated in RS-AML, as was observed in SF3B1mut MDS. These results demonstrate that erythroblasts share ancestry with malignant myeloid blast cells in RS-AML. The genetic background of RS-AML differs from that of RS-MDS, however downstream effector pathways may be comparable, providing a possible explanation for presence of RS in AML. Overall design: RNA sequencing of primary AML samples containing Ringsideroblasts in bone-marrow smears