Abstract LB-519: Chemotaxis of acute promyelocytic leukemia cells toward CXCL12 is involved in ATRA syndrome and the requirement of chemotherapy during Induction therapy with ATRA

Abstract

Abstract We previously reported that treatment of acute promyelocytic leukemia (APL) cells with all-trans retinoic acid (ATRA) in vitro increases the directed migration towards CXCL12. Here we report the clinical significance of this phenomenon. Bone marrow cells were corrected from 13 de-novo APL patients after obtaining informed consent. Flow-cytometric analysis revealed that all cases expressed CXCR4, the receptor of CXCL12. The CXCR4 expression was enhanced after 24 hour treatment with ATRA in vitro. Chemotaxis analysis using Boyden chamber demonstrated that the directed migration towards CXCL12 increased 1.03 to 4.16 (median 1.65) times in ATRA-treated APL cells as compared to non-treated cells. Four out of 13 APL patients developed ATRA syndrome during induction therapy with ATRA. The chemotaxis towards CXCL12 was enhanced in these four patients (p<0.01). Six cases required chemotherapy with IDR and Ara-C during induction therapy with ATRA. The significant increase in chemotaxis toward CXCL12 was also observed in these patients as compared with those who achieved CR by the induction therapy with ATRA alone (p<0.01). Interestingly, the ability of chemotaxis of APL cells appeared to be more well correlated with the occurrence of ATRA syndrome and the requirement of additional chemotherapy during ATRA treatment as compared with other well known predictable factors such as the APL cell number or white blood cell number in the peripheral blood, and the expression level of CXCR4. To investigate the possible mechanism of the chemotaxis, we used APL cell lines such as ATRA-sensitive NB4 cells and ATRA-resistant UF-1 cells as well as primary APL cells. An inhibitory antibody against CXCR4 and pertussis toxin effectively suppressed chemotaxis of APL cells toward CXCL12. Chemotaxis assay using selective signaling inhibitors demonstrated that activation of phospholipase C but not MAP kinase was strongly involved in the directed migration towards CXCL12 in APL cells. Additionally, the Akt-PI3-kinse pathway was partly participated in this chemotaxis. These results suggest that chemotaxis ability of APL cells toward CXCL12 is involved in the pathogenesis of ATRA syndrome and the requirement of chemotherapy during induction therapy with ATRA. Furthermore, specific signal targeted-therapy might contribute to prevent ATRA syndrome and/or avid administration of excessive chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-519. doi:1538-7445.AM2012-LB-519