Myelodysplastic Syndrome (MDS) is driven by a complex combination of genetic mutations that results in heterogeneity in both clinical phenotype and disease outcome. It is known that MDS can progress to leukemia, in particular secondary Acute Myeloid Leukemia (sAML).
Adam S. Sperling, of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, USA, et al. have written an insightful review on the progression of MDS to AML, specifically the clonal evolution of MDS to sAML.
They also report on the variability of the clinical course of the condition, namely that some patients can survive for several years with minimal therapy, whereas others rapidly progress to AML. The review was published in Nature Reviews Cancer in January 2017.
With regards to the progression of MDS to AML, here are the key highlights of the review:
The molecular genetics of MDS
Sperling et al. state that recent work has demonstrated that distinct MDS stem cells bearing the immunophenotype of normal Hematopoietic Stem Cells (HSCs; Lineagelow, CD34+, CD38–, CD90+ [also known as THY1+], CD45RA– [also known as PTPRC–]) are able to sustain the generation of myeloid progenitors in vitro and in vivo, whereas other early myeloid progenitors are unable to do so. Patients who progressed to AML developed multiple new mutations in the leukemic stem cell compartment, coupled with new myeloid progenitor (that is, non-HSC) populations that had gained self-renewal potential.
Progression to leukemia
Sperling et al. affirm that sAML develops from MDS and is biologically distinct from de novo AML. In particular, they report that mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, Enhancer of Zeste 2 (EZH2), BCL6 Co-Repressor (BCOR, part of a polycomb repressive complex [PRC]), and Stromal Antigen 2 (STAG2, a component of the cohesin complex) are strongly associated with an antecedent MDS and are thus highly specific for sAML. In addition, the authors report that some of the mutations that occur during progression from MDS to AML are found in core hematopoietic transcription factor genes including RUNX1, GATA2 and CCAAT/Enhancer Binding Protein α (CEBPA), which abrogate normal differentiation.
Sperling et al. conclude that further understanding of the genetic landscape of MDS and AML will enable the development of refined prognostic staging models. This in turn will lead to the improved identification of the patients most likely to respond to therapy and the development of new targeted therapeutics. The authors hypothesized that specific mutations may predict response to standard therapies such as hypomethylating agents, lenalidomide, and allo-HSCT, but prospective studies are needed to validate these findings.
Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.