Prognostic Significance of Intracellular Survivin in Myeloid Blast Cells As an Inhibitor of Apoptosis in Egyptian Adult Acute Myeloid Leukemia (AML) Patients

Background: The balance between cell death and cell viability is important in tissue homeostasis. Abnormalities in the control of apoptosis play an important role in tumorigenesis ( Altieri Cancer 2013). Survivin is one of eight members of the inhibitor of apoptosis protein family (IAP) that, regulates, integrates cell division and suppresses apoptosis . Over expression of several IAPs has been detected in various hematological malignancies, including acute leukemias, myelodysplastic syndrome , chronic myeloid leukemia , and many types of lymphoid malignancies, such as chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Many publications revealed significant correlation between a high level of IAPs, especially of XIAP and survivin, and tumor progression contributing to leukemogenesis due to deregulated apoptosis. The expression of survivin may be a general feature of cancer and alone or with other antiapoptosis genes such as Bcl-2 , survivin may extend the viability of transformed cells and regulate their susceptibility / resistance to apoptosis-based therapy. For this reason survivin may provide an ideal therapeutic target for its selective expression in neoplasia. Survivin shuttles between the nucleus and the cytoplasm , it effectively inhibits apoptosis, by binding to second mitochondrial activator of caspase ^.Expressed during embryonic development and by many cancer cell types,but not in the differentiated normal tissue ,survivin is implicated in control of cell survival and regulation of mitosis in cancer( Coumar et al Cancer 2013).

Objectives: To assess expression of survivin in Egyptian AML patients^, and its correlation to outcome, impact on progression, and survival.

Methods: 120 adult Egyptianpatients with AML (52 females and 68 males) were recruited and followed up for 2 years, ( mean age:42.1±13.1years) , 16 patients had AML-M0, 32 AML- M1,32 AML- M2, 12 AML- M3, 16 AML -M4 and 12 AML-M5 ( FAB classification ). A control group of 60 age and sex matched normal healthy volunteers was included.

All enrolled patients were treated according to our unit ongoing induction and consolidation regimens(NCCN guidelines). Patients were followed up for two year and outcome was designated as either favorable or unfavorable.Detection of intracellular Survivin antigen in myeloid blast cells was done by flow cytometry on bone marrow samples at D0, D28 and then every 6 month (Kim et al Ann Lab Med 2013).

Results: Survivin expression was higher in AML patients at D0 and D28 compared to healthy controls (P=0.001),highest survivin level were seen in AML M5 ( FAB subtypes) followed by AML M4 ,then by AML M1, AML M0, AML M3 and AML M2 subtype. A statistically significant positive correlation was found between age of patient at diagnosis and Survivin expression, also between survivin level at D0 and at D28 among responders patients (P=0.001), also between D0-survivin level of AML patients with favorable response compared to patients with unfavorable response (P=0.005), survivin expression positively correlated with CD15, CD14 and CD11c expression. No statistically significant correlations were found between survivin expression and sex, or with results of cytogenetic studies ,nor with AML FAB subtypes. There was statistically significant negative correlation between survivin level and with Complete remission (CR) ,overall survival (OS) Figure -1. EFS, and PFS. CRand post induction response to chemotherapy occured in patients with negative survivin expression more than in patients with positive survivin expression (P=0.005),and after 2 year follow up patients with positive survivin expression relapsed more (P=0.015).

Conclusions: Survivin is important factors involved in control of apoptosis in malignant cells. Survivin expression was found to be higher in elderly AML patients compared to younger patients group, A statistically significant negative correlation was detected between survivin level at D0 and CR,OS,EFS, and PFS. Being preferentially and highly expressed in cancer cells, with little expression in normal tissues,makes it an attractive therapeutic target to inhibit cancer growth by inhibiting extrinsic and intrinsic apoptotic pathways and confers resistance to apoptosis by directly suppressing caspase activity.