In this chapter, we detail the genomic alterations that underlie MPNs, with a focus on the recent discovery of mutations in CALR, and explore the clinical and biological relevance of the altered genomic landscape in MPNs.
Patients with JAK2 V617F-positive MPN have a heterogeneous histology while CALR-positive ET is associated with megakaryocyte abnormalities and prefibrotic PMF.
CALR mutations were present in 44% of ET (15/34), 14% of persistent thrombocytosis suggestive of MPN (3/21) and none of the secondary thrombocytosis (0/98).
Genotyping for CALR mutations represents a novel useful tool for establishing a clonal myeloproliferative disorder in JAK2 and MPL wt patients with thrombocytosis and may have prognostic and therapeutic relevance.
Knowledge of the mechanisms by which mutated calreticulin underlie a myeloproliferative neoplasm as well as the clinical and therapeutic implications is just at the very beginning, and exciting times await research in this field.
Myeloproliferative neoplasms (MPNs) are stem cell-derived clonal myeloid malignancies characterized by a unique somatic mutational profile since three mutually exclusive mutations (JAK2V617F, MPL, and CALR) sustain the great majority of the cases.
This assay allows for rapid, convenient screening for CALR mutations in MPNs, thereby reducing the number of cases that require assessment by Sanger sequencing, reducing labor and improving turnaround time.
The recent discovery of frameshift mutations in CALR in approximately 70 % of MPN patients lacking the JAK2 and MPL mutations offers a reliable diagnostic marker for the latter group.
Calreticulin mutation represents the second most frequent mutation after JAK2 V617F in myeloproliferative disorder and is considered to be a driving mutation.
Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes.
Four main molecular types of clonal MPN can be distinguished: JAK2(V617F)-positive ET and PV; JAK2 wild-type ET carrying the MPL(515); mutations in the calreticulin (CALR) gene in JAK2/MPL wild-type ET and MF, and a small proportion of JAK2/MPL/CALR wild-type ET and MF patients.
Calreticulin (CALR) mutations have recently been reported in 70-84% of JAK2V617F-negative myeloproliferative neoplasms (MPN), and this detection has become necessary to improve the diagnosis of MPN.
Although we described a family with carriers of both JAK2V617F and CALR mutations, due to the low number of CALR-mutated familial cases, we could not determinate whether the JAK2 46/1 haplotype predisposes or does not to CALR-mutated familial cMPN.
PCR amplification followed by fragment length analysis is a rapid, sensitive, and specific method for screening persons with MPNs for CALR mutations, especially those with ET and PMF and for estimating mutant allele burden.