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.
Translocations involving the JAK2 locus are of oncogenic importance in acute leukemias, myelodysplastic/myeloproliferative diseases and T-cell lymphomas.
A high JAK2(V617F) allele burden was correlated with the transformation to myelofibrosis (p<0.0001), but not with the transformation 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.
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.
Germ-line p53 mutations are associated with dominantly inherited Li-Fraumeni syndrome (LFS), which features early-onset sarcomas of bone and soft tissues, carcinomas of the breast and adrenal cortex, brain tumors, and acute leukemias.
Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression.
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.
ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies.
Initial p53 mutation screening of blast cells from 29 patients with acute leukaemia by PCR-denaturing gradient gel electrophoresis showed that 2 had a silent codon 213 polymorphism and only the index case had a somatic mutation identified to be an 8 bp insertion in codon 281 (5'CCGGGGGG-3').
Overall, our data suggest that (1) TP53 inactivation is a relatively common event in leukemias with MLL rearrangements irrespective of the leukemic phenotype and of the patients' age; (2) at least two genetic lesions (i.e., MLL rearrangement and TP53 mutation) have accumulated in the short time (few weeks after the birth or conception of the child) corresponding to the development of acute leukemias of infancy.
A cohort of 75 MDS patients were investigated for RAS, FMS and p53 mutations, and these molecular findings were related to cytogenetics, clinical status, transformation to acute leukemia, prognostic scores and survival.
We did not find mutations in GATA1 in leukemic cells of DS patients with other types of acute leukemia, or in other patients with AMKL who did not have DS.