Abstract
Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments.
Highlights
The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal diseases of the hematopoietic stem cell (HSC) that can evolve into secondary acute myeloid leukaemia (AML)
Recurrent cytogenetic aberrations (5q deletion, deletion or monosomy 7, 20q deletion, trisomy 8), genetic mutations affecting epigenetic regulators (TET2, IDH1/2, DNMT3A, ASXL1, EZH2), splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2), transcription factors (TP53, RUNX1), signaling adapters (NRAS, KRAS, JAK2, CBL, KIT) and cohesins (STAG2, SMC1, SMC3) and altered gene expression patterns have been linked to MDS and variably associated with MDS subtypes
These gene mutations or deletions belong to a common set of genetic alterations in cancer, their contribution to disease initiation remains unclear, as the presence of mutations at low allelic burden without cytopenia or bone marrow dysplasia may precede for several years the onset of myeloid malignancies
Summary
The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal diseases of the hematopoietic stem cell (HSC) that can evolve into secondary acute myeloid leukaemia (AML). Recurrent cytogenetic aberrations (5q deletion, deletion or monosomy 7, 20q deletion, trisomy 8), genetic mutations affecting epigenetic regulators (TET2, IDH1/2, DNMT3A, ASXL1, EZH2), splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2), transcription factors (TP53, RUNX1), signaling adapters (NRAS, KRAS, JAK2, CBL, KIT) and cohesins (STAG2, SMC1, SMC3) and altered gene expression patterns have been linked to MDS and variably associated with MDS subtypes These gene mutations or deletions belong to a common set of genetic alterations in cancer, their contribution to disease initiation remains unclear, as the presence of mutations at low allelic burden without cytopenia or bone marrow dysplasia may precede for several years the onset of myeloid malignancies. Epistatic interactions between two or several genes within a clone and further competition between clones participate in disease initiation and progression
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