In the past decades, numerous genes whose mutations contribute to cell transformation and tumor progression have been identified. These oncogenes are involved in almost every pathway used to transfer extracellular signals to the cell nucleus. Recently it has become clear that a fully tumorigenic phenotype depends also on genetic inactivation of tumor suppressor genes, which are involved in the control of proliferation and differentiation. Mutations in the p53 tumor suppressor gene are among the most frequent molecular alterations in human cancers (references 4, 49, and 53 and references therein). The product of the wild-type (wt) p53 gene is a nuclear phosphoprotein that binds DNA (29) and functions as a transcription factor (18). It has also been demonstrated that wt p53 acts directly or indirectly on DNA replication, thus contributing to the maintenance of DNA integrity (31,(34)(35)(36) and genome stability (33, 62). Considerable attention has been focused on the structural changes of the p53 gene and their biochemical consequences. However, the physiological function(s) of wt p53 protein is still uncertain. Transgenic p53-null mice develop normally, indicating that p53 is dispensable for proliferation and differentiation or that its absence can be complemented by other, still unidentified mechanisms (13). However, p53-null mice develop after birth multiple tumors in a variety of tissues (13). This finding is consistent with the notion that p53 acts as a suppressor of the tumorigenic phenotype. Numerous experimental works conducted with different tumor cell lines have supported this conclusion (5, 8; reviewed in reference 43). It was reported that overexpression of wt p53 induces differentiation of some p53-negative leukemia cells such as L12 pre-B lymphoid (52), K562 erythroleukemia (16, 20), and HL-60 promyelocytic (55) cells. Other reports demonstrated that expression of exogenous wt p53 suppresses leukemic phenotypes in different ways. Induction of apoptosis was observed in M1 myeloid leukemia (63) and DP16-1 erythroleukemia (47) cells, and a reduction of the growth rate was observed in Be-13 lymphoblastic leukemia cells (9). These and other results demonstrate that wt p53 protein suppresses several leukemias by acting on cell survival, proliferation, and/or differentiation. However, it is still uncertain whether apoptotic death, growth suppression, and differentiation are final events of different pathways activated by wt p53 or whether wt p53 action is unique and the different effects observed after expression of exogenous wt p53 protein are dictated by different cellular environments. Different neoplasias are the results of different oncogene-activated pathways (48, 50). Thus, wt p53-mediated tumor suppression, by interfering with these signalling pathways, might generate diverse effects that do not imply different wt p53 functions. To test this hypothesis, we tried to reduce the number of variables intrinsic to the use of different leukemia cell lines. For this purpose, we transformed a single cell typ...

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To shed light into the molecular basis of Ph+ acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult Ph+ acute lymphoblastic leukemia patients enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that Ph+ acute lymphoblastic leukemia patients carry 7.8 lesions/case on average, with deletions outnumbering gains (88% vs 12%). The most common deletions were those targeting IKZF1, PAX5 and CDKN2A/B detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of IKZF1 plus CDKN2A/B and/or PAX5 had a significantly worse disease-free survival (24.9% vs 43.3%, p=0.026). The only IKZF1 isoform impacting on prognosis was the dominant negative (p=0.003). Copy number aberrations analysis showed that 18% of patients harbored MEF2C deletions, which were of two types, differing in size: the longer deletions were associated with the achievement of a complete molecular remission (p=0.05) and had a favorable impact on disease-free survival (64.3% vs 32.1% at 36 months, p=0.031). These findings retain statistical significance also in multivariate analysis (p=0.057). KRAS deletions, detected in 6% of cases, were associated with the achievement of a complete molecular remission (p=0.009). These results indicate that in adult Ph+ acute lymphoblastic leukemia a detailed evaluation of additional deletions - including CDKN2A/B, PAX5, IKZF1, MEF2C and KRAS - has prognostic implications and should be incorporated in the design of always more personalized treatment strategies.

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