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.
The oncoprotein inhibitory member of the ASPP family (iASPP) is a key inhibitor of the p53 tumor suppressor and is upregulated in patients with acute leukemia and breast carcinoma.
We demonstrated that acute leukaemia, myeloblastic (AML) and lymphoblastic (ALL), is associated with significantly elevated levels of p53 and Bax mRNA in leukaemic cells.
To gain further insight into the role of P53 network in the evolution of acute leukemias, the P53, MDM2, BCL2 and BAX mRNAexpressions in portion samples from patients with ALL and AML were analyzed using multiplex RT-PCR.
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.
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').
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.
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.
Thus, disruption of regulated p53 expression resulting in lack of detectable p53 mRNA even by RT-PCR occurs in about 30% of cases of AML; however, p53 alterations typical for human solid tumors are an infrequent event in most types of human acute leukemias.
The expression of p53 was studied in 9 cell lines and 17 de novo acute leukemia (9 acute myeloid leukemia [AML], 8 acute lymphoblastic leukemia [ALL]) patients.