Abstract 5848: Histone deacetylase inhibitor selectively targets CD123 positive chemoresistant AML cells
Authors: Bowen Yan, Suming Huang, Yi Qiu
Journal: Cancer Research (2018)

Abstract Acute Myeloid leukemia (AML) is the most common acute leukemia in adults. Chemoresistance remains a major burden for treatment of relapse patient. Studies suggest that AML relapse related to the survival of drug resistant leukemia stem cell (LSC) population. To better understand the mechanism of drug resistance and whether it is correlated to the expression of certain group of LSC surface markers, we collected various human AML cell lines and examined correlations of their IC50 of Ara-C and percentage of individual LSC surface markers in these cell lines. We found that only CD47 (R square = 0.6660, P value = 0.0476) and CD 123 (R square = 0.7421, P value = 0.0275) are positively correlated to chemoresistance. In order to rule out heterogeneous genetics background contribute to chemoresistance of cell lines, we generated a resistant cell line from a drug sensitive AML cell line, OCI-AML2, by gradually increased the Ara-C concentration in culture media. During the selection, the percentage of cells with CD47 and CD123 gradually increased. When the resistant cell line is established, the percent of CD123 positive cells are over 90 percent. RNA-seq analysis shows that genes related to cell cycle regulator and resistance of apoptosis changed significantly. However, signature genes that related to stemness, such as Oct4, Nanog, KLF4, Myc, FLT3, are no significant changed in resistant cells compare with the sensitive line, although Sox2 increased 50% and ALDH1A3 increased 3 folds. Therefore, chemoresistant cells may represent cells in a slow growing, de-differentiate stage, however, they may not bare all characteristics of LSCs. We further investigate the role of epigenetic factors in regulating the survival of chemoresistant leukemia cells. Our data shows epigenetic drugs that targeting histone deacetylases, bromodomain proteins and PRC1 complex are effective to induce apoptosis and cell death of chemoresistant cells, therefore they may be potential second line of chemotherapy drug for chemoresistant patients. Histone deacetylase inhibitor Romidepsin efficiently cleared chemoresistant AML blast in xenographed NSG mice. Furthermore, we found Romidepsin has synergetic effect when combine with Ara-C. Interestingly, Romedepsin preferentially target CD123 positive, slow growing cells while Ara-C mainly target fast growing, CD123 negative cells. Therefore, combine treatment with Romedepsin and Ara-C may prevent the development of chemoresistance in AML cells. In summary, we identify CD123 and CD47 cell surface markers may potentially serve as biomarker for chemresistance AML cells. Our study also sheds light on a new mechanism of drug resistance in leukemia, and provide a rationale to develop and test epigenetic-targeted therapies in leukemia, especially in drug resistant relapse patients. Citation Format: Bowen Yan, Suming Huang, Yi Qiu. Histone deacetylase inhibitor selectively targets CD123 positive chemoresistant AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5848.