New insights in myeloid malignancies: application of massive genomics approaches for diagnosis and monitoring

Laburpena

Myeloid malignancies are clonal diseases originated of genetic alterations in hematopoietic stem or progenitor cells. Application of next-generation sequencing to myeloid leukemia has already yielded important discoveries, including the identification of common gene mutations (eg, IDH1 and DNTM3A). However, these efforts have so far excluded rare myeloid disorders. In this work we used a systematic genomic strategy based on whole-exome sequencing, RNA sequencing and target resequencing approaches to provide deeper insights into the genetic pathogenesis of blastic transformation of chronic myeloid leukemia, chronic neutrophilic leukemia and blastic plasmacytoid dendritic cell neoplasm. We identified mutations responsible for these diseases that occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. FLT3, RAS), transcription factors (e.g. IKZF family, RUNX1, ZEB2), epigenetic regulators (e.g. ASXL1, DNMT3A, IDH1, IDH2, TET2), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. LUC7L2, SF3B1, U2AF1). First, our data suggest that sequencing a wider panel of genes that includes ASXL1, TP53 and IKZF gene family could be beneficial in the clinical management of non-responders chronic myeloid leukemia patients, while current diagnostic procedures recommend the study of ABL1 mutations. Second, we show the concurrence of several genetic mechanisms that cooperate with the CSF3R mutation in chronic neutrophilic leukemia, such as U2AF1, TET2, LUC7L2 and ASXL1 mutations, an altered pattern of splicing in RUNX1 gene and an expressed fusion gene PIM3-SCO2. Third, we found that dendritic cell leukemia has a mutational profile strikingly similar to that of other well-defined myeloid leukemias and patients with mutations in genes in the methylation pathways had a significantly reduced cumulative survival. In conclusion, large-scale sequencing efforts allowed us the establishment of a comprehensive repertoire of these mutations, contributing to an improvement in the definition and classification of these myeloid malignancies, and to the identification of new prognostic markers and therapeutic targets.