The clinical significance of caspase regulation in acute leukemia

Disruptions of pathways of programmed cell death, ol apoptosis, are increas ingly found in malignant cells of both solid and hematologic neoplasms. Cas pases belong to a family of cysteine proteases and have emerged as central regulators of the apoptotic cascade. Despite many and diverse signals that can trigger apoptosis. the execution of apoptosis appears to be uniformly m ediated through activation of caspase enzymes. Inapproriate expression of c aspases or malfunctions in their regulation through other pathways may also be on important step in the pathogenesis of acute leukemias. Recent studie s have shown that overexpression of the inactive forms of caspases CPP32 (c aspase 3) and ICH-1 (caspase 2) is frequently observed in the blasts of pat ients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (A LL). Many other enzymes involved in apoptosis are expressed at high levels in patients with acute leukemia. Whether this signals the capacity of leuke mic cells to rapid induction of apoptosis with fast reduction of the burden of disease and favorable clinical outcome, or accumulation of inactive sub strates, that cannot be activated by lack of cellular mechanisms to do so. requires further investigation. With the identification of many other regul ators of apoptotic activity in the leukemic cells, new targets for future t herapy may be identified and many new insights can be gained in understandi ng the biological behavior of response and resistance to therapy as well as control and relapse from minimal residual disease.