Ricerc@Sapienza

Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell-derived disorders, including polycythemia vera (PV), essential thrombocytemia (ET) and primary myelofibrosis (PMF), spontaneously evolving in acute myeloid leukemia. The genetic basis of these diseases are somatic driver mutations, occurring on Janus kinase 2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia (MPL) genes, all deregulating the JAK2/STAT signaling pathway. Whereas JAK2 and MPL mutations are related to essential pathways of myelopoiesis, CALR mutations affect a multifunctional protein, apparently not connected with hematopoiesis.
CALR mutations occur in ET or PMF subjects, but are rare or non-existent in PV. They consist of a wide-variety of deletions and insertions in exon 9, all resulting in a 1-bp frameshift, which removes the ER retrieval motif KDEL and converts the first 31 bases of CALR 3¿UTR into coding sequence. We recently detected a novel exon 9 deletion in an evolutionarily conserved CALR 3¿UTR region, designated c.1254+10_+33del24, in two siblings diagnosed with JAK2V617F-negative PV. This mutation occurred 10 bp downstream the CALR stop codon, thus not altering the coding sequence, but leading to overexpression of CALR and to erythrocytosis.
The scope of this project is to elucidate the role of CALR 3¿UTR sequence in normal myelopoiesis and MPNs, inspecting regulation orchestrated by miRNA and complex regulative functions of 3¿UTR, such as mRNA or protein localization and translation efficiency. As additional degree of complexity, RNA editing of CALR mRNA is studied in relationship with 3¿UTR functions, since it can affect them modifying RNA complementarity without changing genomic sequence. By exploring these unknown aspects of MPNs in primary samples from normal donors and MPN patients, we may shed light on new mechanisms of hematopoiesis, which are deregulated in MPNs, revealing useful cues for the design of novel targeted treatments.