ALDH1A1 induces resistance to CHOP in diffuse large B-cell lymphoma through activation of the JAK2/STAT3 pathway

Jinqiong Jiang, Yiping Liu, Youhong Tang, Li Li, Ruolan Zeng, Shan Zeng, Meizuo Zhong Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China Abstract: Increasing evidence has shown that aldehyde dehydrogenase 1A1 (ALDH1A1), a detoxifying enzyme, is responsible for chemoresistance in a variety of tumors. Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), chemoresistance is a common cause of treatment failure. This study aims to investigate the significance of ALDH1A1 expression and the mechanism by which ALDH1A1 is involved in the chemoresistance of DLBCL cells. ALDH1A1 expression was assessed in 88 DLBCL tissues by immunohistochemistry. The association between ALDH1A1 expression and outcome was evaluated. We also investigated the effect of ALDH1A1 on CHOP resistance in DLBCL cells using functional analysis. ALDH1A1 expression levels were upregulated in patients with stable or progressive disease after CHOP and its expression positively correlated with expression of STAT3 and p-STAT3. In keeping with these observations, ALDH1A1 expression was significantly associated with short survival of DLBCL patients who received CHOP chemotherapy. In functional assays in Pfeiffer cells, overexpression of ALDH1A1 conferred resistance to CHOP, while silencing of ALDH1A1 using short hairpin RNA had the opposite effect. Furthermore, we also observed that ALDH1A1 could regulate the JAK2/STAT3 pathway, while inhibition of the JAK2/STAT3 pathway by WP1066 negated the effect of ALDH1A1 overexpression. These observations reveal that ALDH1A1 induces resistance to CHOP through activation of the JAK2/STAT3 pathway in DLBCL, and its targeting provides a potential strategic approach for reversing CHOP resistance. Keywords: ALDH1A1, diffuse large B-cell lymphoma, CHOP, chemoresistance, JAK2/STAT3 pathway