These mutations include JAK2, CALR and MPL mutations as the main disease drivers, mutations driving clonal expansion, and mutations that contribute to progression of chronic MPNs to myelodysplasia and acute leukemia.
A high JAK2(V617F) allele burden was correlated with the transformation to myelofibrosis (p<0.0001), but not with the transformation to acute leukemia.
Translocations involving the JAK2 locus are of oncogenic importance in acute leukemias, myelodysplastic/myeloproliferative diseases and T-cell lymphomas.
JAK2V617F mutation was detected after transformation to CMML in 1 of them; in the other, a novel translocation t(5;12)(p13;q24) was observed at the time of progression to acute leukemia.
Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma.
ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies.
Despite this progress, many questions remain unsolved, including how a single JAK2 mutation causes three different MPD phenotypes, what other genes might be involved in the pathogenesis, and what are the factors determining the progression to acute leukemia.
Activation of JAK2 by chromosomal translocation or point mutation is a recurrent event in hematopoietic malignancies, including acute leukemias and myeloproliferative disorders.
A translocation generating the constitutively activated fusion protein PCM1-JAK2 has also been recently found in atypical chronic myelogenous leukemia and acute leukemia.