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.