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Personalized management of MDS
logical imbalances have been identified, in particular with- in the T-cell lineages. In lower-risk MDS, an upregulation of cytotoxic T cells has been observed, whereas higher- risk MDS is characterized by immune escape and upregu- lation of regulatory T cells.34-36 Several studies have identi- fied autonomous large granular lymphocyte T-cell clones in a large proportion of patients with MDS.37,38 Similarly, the presence of plasma cell clones has been described.39,40 Whether the MDS disease is evoking immune activation or whether an initial immune activation results in selec- tion pressure giving mutated MDS cells a survival advan- tage is unclear.
The microenvironment in MDS shows abnormal mor- phological features. Molecular characterization of stromal niche cells has revealed various alterations, including dis- turbances in differentiation and in stem cell supporting functions.41-46 47-49 Again, whether niche-alterations are initi- ating events or induced by the MDS clone is unknown. Murine models have suggested that manipulation of the niche can induce myeloid malignancies, but solid evidence from MDS patients remains to be presented.50-52
An important route to develop MDS is by exposure to cytostatic drugs or radiation-therapy, i.e., therapy-related MDS. The mechanisms involved are largely unknown. Case-control studies have demonstrated a higher frequen- cy of underlying CHIP clones in patients developing ther- apy-related MDS.53-55 Possibly, the survival pressure that is exerted on hematopoietic stem cells during treatment may give underlying CHIP clones a survival advantage resulting in emergence of the MDS. It has also been proposed that cytostatic/radiation therapy can cause direct DNA dam- age but evidence for this hypothesis is sparse.
5q- syndrome
Although the mechanisms underlying anemia in patients with del(5q) remain elusive, haploinsufficiency and dependence of erythroid cells on casein kinase (CK1α), encoded for by a gene within the common delet- ed region of del(5q), appear to be of central importance. The drug lenalidomide induces ubiquitination of CK1α through the E3 ubiquitin ligase cereblon, resulting in CK1α degradation.56 Such degradation in the haploinsuffi- cient del(5q) cells sensitizes these cells to lenalidomide, providing a basis for the therapeutic effects of the drug in these patients. Additionally, the E3 ubiquitin ligase RNF41 is a principal target responsible for erythropoietin receptor (EpoR) stabilization. Data suggest that lenalidomide also
Table 4. Mutations in myelodysplastic syndromes.
has E3 ubiquitin ligase inhibitory effects thus inhibiting RNF41 auto-ubiquitination and promoting membrane accumulation of signaling competent JAK2/EpoR com- plexes that augment responsiveness to erythropoietin.57
Myelodysplastic syndrome with ringed sideroblasts and SF3B1 mutations
The characteristic mitochondrial ferritin accumulation in MDS-RS is associated with reduced expression of the iron transporter protein gene ABCB7.58,59 In two pivotal papers, Papaemmanuil et al. and Yoshida et al. described recurrent mutations in splicing factor 3b subunit 1 (SF3B1) in more than 80% of patients with MDS-RS.60,61 Subsequent studies identified aberrant splicing of genes involved in erythro- poiesis and mitochondrial function, but the molecular and cellular links between the SF3B1 mutation and ineffective erythropoiesis remain elusive.62-64 Recent studies have tracked back the SF3B1 mutations to multipotent hematopoietic stem cells and described how MDS-RS ery- thropoiesis can be confidently modeled in vitro, leading to new possibilities to assess the effects of novel com- pounds.65,66 From a clinical perspective MDS-RS with SF3B1 mutations appears as a clinically and morphologically dis- tinct entity with affected patients having a favorable sur- vival, a low risk of leukemic transformation but a high risk of developing refractory transfusion dependence.6,67
Genetic predisposition to myeloid neoplasms
Myeloid neoplasms with germline predisposition were recognized as a separate entity in the WHO 2016 classifi- cation.1 Individuals with germline predisposition exhibit an increased risk of developing myeloid neoplasms, main- ly AML and MDS. Estimates suggest that at least 5% to 15% of patients with MDS or AML carry germline patho- genicvariants.68,69
Germline mutations are divided into those predisposing to myeloid neoplasms without a pre-existing disorder, mutations with pre-existing platelet dysfunction, and mutations associated with organ dysfunction. GATA2 and RUNX1 mutations are relatively common and mandate continuous surveillance of asymptomatic carriers, because of the high risk of such subjects developing a myeloid neo- plasm.21,68,70 Mutations in the telomerase complex usually lead to a complicated clinical presentation with multi- organ involvement, and mutations in the SAMD9 and SAMD9L genes are associated with a high risk of progres- sion to monosomy 7 MDS.71,72 More recently identified
Functional group
DNA methylation
Chromatin modification Cohesin complex formation RNA splicing
Transcription
Cytokine receptor/tyrosine kinase Other signaling
Checkpoint/cell cycle
DNA repair
Other
Included genes
DNMT3A, TET2, IDH1, IDH2
EZH2, SUZ12, EED, JARID2, ASXL1, KMT2, KDM6A, ARID2, PHF6, ATRX STAG2, RAD21, SMC3, SMC1A
SF3B1, SRSF2, U2AF1, U2AF2, ZRSR2, SF1, PRPF8, LUC7L2 RUNX1,ETV6,GATA2,IRF1, CEBPA, BCOR, BCORL1, NCOR2, CUX1 FLT3, KIT, JAK2, MPL, CALR, CSF3R
GNAS, GNB1, FBWX7, PTEN TP53, CDKN2A
ATM, BRCC3, FANCL NPM1, SETBP1, DDX41
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