Aberrant Proliferative and Apoptotic Pathways in Acute Lymphoblastic Leukemia (ALL):Molecular Therapies to Overcome Chemo-Resistance.

Adult acute lymphoblastic leukemia (ALL) is characterized by a high relapse rate, with the majority of patients developing chemo-resistance and ultimately dying of the disease with a 5-year survival rate of 40% (Faderl et al., 2010). Significant advances, however, have been made in cases carrying the acquired genetic alteration BCR-ABL (ALL-Ph+) targeted by tyrosine-kinase inhibitors (Ottmann & Pfeifer, 2009). Therefore, several studies have recently been carried out to look for additional, therapeutically exploitable, genetic lesions. Aberrant activation of signal transduction pathways (STP) implicated in proliferation and survival mechanisms are generally involved in leukemogenesis and drug resistance (Zhao et al., 2010). Genes in the PI3K/PTEN/AKT/mTOR, RAS/RAF/MEK/ERK, and Jak/STAT pathways are frequently mutated and their expression is often altered in hematopoietic malignancies, including ALL (McCubrey et al., 2011; Steelman et al. 2008). In addition, deregulation of survival mechanisms may confer chemo-resistance to leukemic cells, particularly involving alterations of the Bcl-2 signaling cascade, which may represent one of the most important, potentially druggable, pathways for therapeutic intervention in ALL. Starting from our studies on chemo-resistance in ALL, particularly on multidrug resistance (MDR1) expression and prognostic significance, in this chapter we will illustrate the major pathways aberrantly activated in ALL - PI3K/PTEN/AKT/mTOR, RAF/RAS/MEK/ERK, and the Bcl-2 family of proteins - with the ultimate goal of summarizing novel targets for molecular therapies, especially in resistant/refractory cases. Controversies on and potential benefits of novel approaches based on STP inhibitors will be discussed. Epigenetic changes will be examined to address their importance in association with post-translational modifications. Future perspectives will encompass review of Reverse Phase Protein Arrays (RPPA) as a promising new tool for translational studies in clinical sample series, helping define the functional proteomic profile at steady-state; this approach may lead to the identification of aberrant molecular target(s), possibly guiding the choice of specific molecular therapies, on one hand, and leading to the elucidation of post-treatment changes, on the other, with the overall objective of improving the strategies currently employed to counteract leukemia chemo- and targeted drug-resistance.