Expression Of Livin And Smac In Acute Leukemia And Clinical Significance

Background and Objective Apoptosis or Programmed cell death, is an activemechanism of cell death controlling the development and homeostasis of multicellular organisms and inhibiting cancer cells. Tight regulation is required to ensure a delicate balance of life and death. Several types of molecules are known to interfere with apoptosis, for example cellular gene, proteases and signaling pathways. Two apoptotic pathways have been described. One, Reaper, Smac/DIABLO and HtrA2, is initiated cellapoptosis. Two, Bcl-2, CrmA, P35 and IAPs, is antiapoptosis. The major regulators of caspases are the IAPs or inhibitors of apoptosis proteins. The IAPs include XIAP,c-IAP1,C-IAP2,NAIP,Apollon,Livin,Survivin,ILP-2. Livin gene is located at chromosome 20q13.This gene is 4.6kb. It contains a single BIR domain at the NH2 terminus as well a COOH-terminal RING domain and encodes two splicing variants, Livin a and p. The two proteins are highly similar, except for 18 amino acids located between the BIR and the RING domains. The mRNA for Livin was not detectable in most normal adult tissues with the exception of the placenta, but was present in developmental tissues and in several tumors . Livin served as a new target for apoptosis-inducing therapy of cancer. But the research on the function of Livin in hematological malignance is just on the beginning, the studies reported are mainly on the leukemic cell lines and rarely on the primary leukemic cells. Smac/DIABLO (second mitochondria-derived activator of caspase or direct IAP binding protein with low pI) is a protein released from mitochondria in response to apoptotic stimuli along with cytochrome c, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway and functions as a direct endogenous inhibitor of IAP proteins. Smac is translated as a 239 residues precursor protein with a mitochondrial targeting sequence at its N-terminus that is removed upon import. Although it resides within the intermembrane space of mitochondria in healthy cells, upon cellular stress such as UV irradiation, DNA damage and growth factor depletion Smac is released into the cytosol where it acts as a sensitizer for caspase acting by binding to IAPs via a short N-terminal sequence that disrupts binding of caspase to the IAPs BIR domain. The relationship between Livin and Smac on acute leukemic(AL) cells will be analyzed in this study.Methods:The mRNA expressions of Livin and Smac in 52 AL adult patients with acute leukemic(AL) (including de novo acute leukemia patients, relapsed patients and complete remission patients), were measured by reverse transcription polymers chain reaction ( RT-PCR). Other healthy 10 adults were selected as normal controls (NC).Results:1 The expression rate of Livin mRNA in newly diagnosed acute leukemia (AL) patients was higher than that of healthy controls(40.3% versus 0%) (P<0.05). The expression rate of Livin mRNA in acute myelogenous leukemia(AML) (42.1%) was higher than that of acute lymphocytic leukemia(ALL) (35.7%) without statistical significance (P > 0.05). The expression rate of Livin mRNA in relapsed patients (50.0% ) was higher than that of healthy controls (P < 0.05). The expression rate of patients in remission patients (0%) was lower than AL group(P<0.05).2 The positive rate of Smac mRNA in newly diagnosed AL patients was higher than HC group (59.6% versus 10.0%)(P < 0.05). The positive rate in AML(60.5%) and ALL (57.1%) had no stastifical difference (P > 0.05). The positive rate of Smac in relapsed patients(60.7%) was higher than that of HC group and remission patients' (P < 0.05). The difference between relapsed patients and newly diagnosed AL had no statistical significance (P > 0.05). The positive rate of Smac in remission patients(14.2% ) was higher than that of HC group without statistical significance (P> 0.05),and it is lower than AL patients'(P<0.05).1.3 In newly diagnosed acute leukemia patients, the level of Livin mRNA was associated with that of Smac ( P<0.05).1.4 The complete remisson rate (CR) Livin+ AL patients achieved after induction therapy was lower than that of Livin- AL patients (38.9% versus76.9%)( P< 0.05). The CR rate of Smac+ AL group is lower than that Smac- of group (40.0% versus 85.7%) (P < 0.05). The CR rate of Livin-Smac- group was higher than that of Livin+ Smac+ group (100% versus 40.0%)( P < 0.05).Conclusions:1 The expression of Livin mRNA in newly diagnosed acute leukemia patients was significantly higher than that of healthy controls, while they decreased in pailents at complete remission(CR). In relapsed patients, the expression of Livin gene increased again. The CR rate of Livin - group was higher than that of Livin + cases, indicating that Livin may be involved in the genesis and progression in AL. Its high expression predicts poor prognosis.2 The level of Smac mRNA in newly diagnosed acute leukemia patients was also significantly higher than that of healthy controls. The high expression of Smac mRNA was associated with high Livin, suggesting that Smac performs its proapoptotic acting through inversion of the antiapoptotic effect of Livin.