Molecular basis of MDS/MPN overlap syndrome
Previously known as refractory sideroblastic anemia with thrombocytosis (RARS-T), MDS/MPN-RS-T manifests with clinicopathological features of refractory anemia with ring sideroblasts and essential thrombocythemia (ET). This predictably translates into prognosis that is better than that seen in patients with MDS but worse than in those with ET. For instance, this entity has a better overall survival and a lower rate of leukemic transformation as compared to MDS-RS-SLD, both of which are worse compared to ET 3. Now fully characterized in the newest WHO, the molecular basis for the dual nature of this entity has been elucidated and includes mutation of driver genes that result in myeloproliferation as well as myelodysplasia. The decreasing rank order of such mutations include SF3B1 , JAK2, ASXL1, DNMT3A, andSETB1 . Up to 50% of the affected patients harbor the first two mutations simultaneously4,5. Specifically splicing factor 3 binding partner 1 (SF3B1), which resides in the spliceosome complex, is mutated in approximately 80% of these patients and results in abnormal splicing of the mitochondrial iron transporterSLC25A37 . 6 Consequentially, ring sideroblasts and ineffective erythropoiesis are seen and translate clinically to anemia. Found in myeloproliferative neoplasms among others, Janus kinase 2 mutation is seen up to 60% of MDS/MPN-RS-T patients. The wild type protein is a non-receptor tyrosine kinase mediating a proliferative response to erythropoietin, thrombopoietin and granulocyte colony stimulating factor (GCSF) by acting on their appropriate receptors. The downstream effectors include the mitogen activated protein and phosphoinositide 3 kinases (MAPK, PI3K respectively) as well as the signal transducer and activator of transcription (STAT) pathways7,8 . Unregulated, factor independent constitutive activation of these pathways is the basis of the myeloproliferation seen in these neoplasms. Alternatively, and in place of JAK2 , a frameshift mutation of the calreticulin molecule (CALR ) can cause deletion of a KDEL sequence found on the wild type protein. The resultant mutant binds to the N-glycosylated extracellular domain of the thrombopoietin receptor similarly causing the mitogen independent and persistent activation of the STAT5, MAP and PI3/AKT pathways9,10. A mutation in myeloproliferative leukemia protein (MPL ; alternatively known as CD110 or thrombopoietin receptor) itself can cause a similar outcome 11,12. The extent of gene expression is tightly regulated and aberrancy in molecular mechanisms that achieve these mechanisms can cause genetic dysregulation and oncogenesis. One such mechanism includes methylation, acetylation or phosphorylation of DNA packaging histones that organize the chromatin into nucleosomes. Polycomb Repressive Complex 2 (PRC2) encoded by Enhancer of Zeste Homologue2 (EZH2 ) is the catalytic domain of the Histone H3 lysine 27 methyltransferase. Additional of Sex Combs-like (ASXL1 ) is a related protein that recruits PRC2 complex resulting in histone modification. Its loss of function by mutation results in loss of polycomb repression and myeloid transformation . DNA methyl transferase 3A (DNMT3A ) adds a methyl group to 5´cytosine in CpG causing global gene silencing via formation of 5-methylcytosine. Ten-Eleven translocation 2 (TET2 ) causes the demethylation of DNA by converting the resultant 5-methyl cytosine via hydroxylation . Isocitrate dehydrogenase 1/2 (IDH1/2 ) provide the α-ketoglutarate required for this reaction. Mutations in any of these actors can functionally decrease the resultant DNA methylation and gene silencing triggering myeloproliferation 13-15.