Inactivation of SHIP1 in acute lymphoblastic leukemia.

摘要

Despite the success of treatment of acute lymphoblastic leukemia (ALL), the most common childhood cancer, 20% of cases continue to relapse and others suffer from secondary malignancies. The PI3K/Akt pathway is central to cell survival. Deregulation of this pathway, through PI3K and PTEN mutations, is often found in many cancers. In ALL, though Akt is deregulated, PI3K and PTEN mutations are infrequent, suggesting that other factors are responsible. The phosphatase, SHIP1, acts similarly to PTEN in regulation of Akt activity. In this study, SHIP1 in B- and T-cell ALL is found to be translationally inactivated through alternative splicing and mutations. In primaries, wild-type SHIP1 protein is undetectable, and instead, truncated forms are found. Mutational analysis of the SHIP1 reveals alterations that include deletions and insertions resulting in silent and missense mutations in functional regions of the gene, which explain the loss of full-length protein and render the variants dysfunctional. Analysis of PTEN expression shows either deletion or inactivation in ALL. The deregulation of both PTEN and SHIP1 in ALL substantiates the Akt pathway as an important target for therapeutics. Limited success in treatment is likely due to poor understanding of how oncogenic pathways are deregulated. To elucidate the role of SHIP1 in chemosensitivity, LY294002 and doxorubicin were studied in SHIP1-expressing and non-expressing cell lines. The presence of SHIP1 is shown to potentially elicit greater responses to drugs. This supports the importance of SHIP1 in determining drug sensitivity and potentiates its use as a tool for determining future therapeutic protocols.