CD157 REGULATES THE SENSITIVITY OF ACUTE MYELOID LEUKEMIA CELLS TO CHEMOTHERAPY BY MODULATING THE APOPTOTIC RESPONSE

Background Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the expansion of immature myeloid cells. Patients survival is low due to the occurrence of chemoresistance and tumor relapse. However, mechanisms underlying drug resistance in AML patients are still largely unknown. Therefore, to clarify the molecular basis of drug resistance and to identify novel markers with potential clinical utility represent an urgent need. CD157, an adhesion molecule expressed by myelomonocytic cells, bone marrow stromal cells and selected epithelial cancers, was found expressed in more than 90% of AML both at diagnosis and after relapse, although at variable levels. In this study we investigated i) the role of CD157 in drug response, and ii) explored the intracellular pathways underlying the functional properties of CD157 in AML cells. Materials and Methods U937, THP-1 and OCI-AML3 AML cell lines engineered for the expression of CD157 as well as fresh AML blasts were used for functional studies by means of the SY11B5 agonistic anti-CD157 monoclonal antibody (mAb). The viability of cells treated with Cytarabine (AraC) alone or in combination with S63845 (a specific inhibitor of Mcl-1 anti-apoptotic protein) was assessed by PrestoBlue and Annexin V/PI assays. Intracellular signaling pathways were analysed by Western Blot and Flow Cytometry. Results Ligation of CD157 by SY11B5 mAb elicited a time- and dose-dependent pro-survival effect, compared to the isotype-matched control mAb, both in fresh AML blasts and cell lines. This effect was accompanied by activation of the PI3K/Akt/Bcl-2 pathway leading to increased resistance to apoptotic signals and AraC treatment. Consistent with these results, knockdown of CD157 enhanced AML cell sensitivity to nutrient deprivation and AraC cytotoxicity. Furthermore, CD157-positive cells treated with AraC showed a remarkable increase of Akt phosphorylation and decreased cleavage of the pro-apoptotic Bax protein, counterbalanced by increased expression of the anti-apoptotic Mcl-1 protein, compared with CD157-negative cells. Combined treatment with S63845 and AraC restored the sensitivity of CD157-positive cells. Conclusion Overall, these results demonstrate an essential role of CD157 as a regulator of survival, stress resistance and drug response in AML blasts, and suggest a potential clinical utility of CD157 as biomarker to guide treatment with new combinatorial therapeutic strategies to circumvent drug resistance.